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Role of Indole Scaffolds As Pharmacophores in The

Role of Indole Scaffolds As Pharmacophores in The

molecules

Review Role of Scaffolds as Pharmacophores in the Development of Anti-Lung Agents

Jyothi Dhuguru and Rachid Skouta *

Department of Biology, University of Massachusetts, Amherst, MA 01003, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-413-577-4167

 Received: 13 February 2020; Accepted: 30 March 2020; Published: 1 April 2020 

Abstract: Lung cancer is the leading cause of death in men and women worldwide, affecting millions of people. Between the two types of lung , non-small cell lung cancer (NSCLC) is more common than small cell lung cancer (SCLC). Besides surgery and radiotherapy, is the most important method of treatment for lung cancer. Indole scaffold is considered one of the most privileged scaffolds in heterocyclic chemistry. Indole may serve as an effective probe for the development of new drug candidates against challenging diseases, including lung cancer. In this review, we will focus on discussing the existing indole based pharmacophores in the clinical and pre-clinical stages of development against lung cancer, along with the synthesis of some of the selected anti-lung cancer drugs. Moreover, the basic mechanism of action underlying indole based anti-lung cancer treatment, such as protein kinase inhibition, histone deacetylase inhibition, DNA topoisomerase inhibition, and tubulin inhibition will also be discussed.

Keywords: lung cancer; indole; non-small cell lung cancer; kinase inhibition; apoptosis; DNA topoisomerase, histone deacetylase inhibition

1. Introduction Lung cancer remains the deadliest disease on record, with approximately 2.09 million new cases reported each year. According to the World Health Organization, it is responsible for 1.7 million cancer deaths worldwide per year [1]. There are two major types of lung cancer: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Among these two types of lung cancers, NSCLC is responsible for approximately 80%–90% of cancerous tumors [2,3]. NSCLC is further divided into three major histological subtypes: squamous-cell carcinoma, adenocarcinoma, and large-cell carcinoma. SCLC and squamous-cell carcinoma are strongly linked to smoking, while adenocarcinoma is the most common type of lung cancer in patients who have never smoked [4]. Treatment of lung cancer is commonly addressed by surgical removal of the affected area and by chemotherapy, which applies a combination of one or more drugs in conjunction with radiation therapy. However, multidrug resistance and the severe side effects associated with chemotherapy persists as one of the major challenges in the treatment of lung cancer.

1.1. Indole and its Pharmacological Significance Indole is a pervasive and naturally occurring , the structure of which comprises of a six-membered ring tethered to a five-membered ring [5] (Figure1). With its 10 π-electrons, indole follows Huckel’s rule of . It is more prone to electrophilic substitution reactions similar to the benzene ring. Molecular orbital studies showed that the 3-position of indole is more reactive towards the electrophilic substitution reactions. can undergo N-substitution reactions under basic conditions owing to the slightly acidic nature of the—NH bond in

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[7]. Due to the diverse applications of the indole scaffold in both the biological and pharmacological fields, hundreds of synthetic schemes were published. The most prominent and widely used ones are Molecules 20202019,, 2524,, 1615x FOR PEER REVIEW 2 of 2526 those reported by Fisher [8], Bischler [9], Hemetsberger [10], Nenitzescu [11], Bartoli [12], and others [13,14]. [7]. Due to the diverse applications of the indole scaffold in both the biological and pharmacological indoleOwing [6]. The to firstits bioavailability synthesis of indole and waspharmacological accomplished applications, in 1866 by Adolf indole von is Baeyer considered [7]. Due the tomost the fields, hundreds of synthetic schemes were published. The most prominent and widely used ones are privileged scaffold in heterocyclic chemistry with such widespread applications as antiviral, diversethose reported applications by Fisher of the [8], indole Bischler scaff [9],old Hemetsberger in both the biological [10], Nenitzescu and pharmacological [11], Bartoli fields,[12], and hundreds others of[13,14].antimicrobial, synthetic schemes anti-inflammatory, were published. anti-cancer, The most prominentanti-hypertensive, and widely anti-diabetic, used ones and are those reported [15– by Fisher17]. Owing [8], Bischler to its bioavailability [9], Hemetsberger and [ 10pharmacological], Nenitzescu [11 applications,], Bartoli [12 ],indole and others is considered [13,14]. the most privileged scaffold in heterocyclic chemistry with such widespread applications as antiviral, antimicrobial, anti-inflammatory, anti-cancer, anti-hypertensive, anti-diabetic, and antioxidant [15– 17].

FigureFigure 1.1. Structure of indole. Owing to its bioavailability and pharmacological applications, indole is considered the most 1.2. Natural Abundance of Indoles privileged scaffold in heterocyclic chemistry with such widespread applications as antiviral, antimicrobial,Naturally anti-inflammatory, occurring indole anti-cancer, derivatives,Figure 1. anti-hypertensive, Structure such as of indole.glucobrassicin anti-diabetic, and andindole-3-carbinol, antioxidant [15– 17are]. commonly found in cruciferous vegetables like cabbage, broccoli, and sprouts [18]. Indole-3-carbinol 1.2.and Natural its dimeric Abundance product of 3,3’-diindolylmethaneIndoles have been found to induce apoptosis in cancer cells [18]. This is a property that has increasingly commanded the attention of researchers from around Naturally occurringoccurring indole indole derivatives, derivatives, such such as glucobrassicin as glucobrassicin and indole-3-carbinol, and indole-3-carbinol, are commonly are the world. To get the greatest benefits, indole rich sources belonging to the Brassica family are foundcommonly in cruciferous found in cruciferous vegetables vegetables like cabbage, like broccoli,cabbage, andbroccoli, sprouts and [sprouts18]. Indole-3-carbinol [18]. Indole-3-carbinol and its particularly recommended by the National Cancer Institute to reduce the risk of cancer [18]. dimericand its dimeric product product 3,30-diindolylmethane 3,3’-diindolylmethane have been have found been to inducefound apoptosisto induce inapoptosis cancer cells in cancer [18]. This cells is a[18]. property TryptophanThis is that a property has containing increasingly that hasindole commanded increasingly is an essential the commanded attention amino ofacid the researchers foundattention in from many of researchers around natural the resources. world.from around To It get is thealso greatestworld. a biosynthetic benefits,To get theprecursor indole greatest rich for sourcesbenefits, the , belonging indole rich to5-hydroxy-, the sources Brassica belonging family are toan particularly theimmediate Brassica recommended precursor family are of byparticularlyserotonin the National (Figure recommended Cancer 2). Institute by the to National reduce the Cancer risk of Institute cancer [to18 reduce]. the risk of cancer [18]. Tryptophan containingcontaining indole is an essentialessential found in manymany naturalnatural resources.resources. It is also a biosynthetic precursor for thethe tryptamine,tryptamine, 5-hydroxy-tryptophan,5-hydroxy-tryptophan, an immediate precursor of (Figure2 2).).

Figure 2. Indole scaffold in biologically important compounds.

Serotonin (5-hydroxytryptamine) is an important associated with the transmission of nerve impulses. It further serves as a precursor to , a neuro-hormone Figure 2. IndoleIndole scaffold scaffold in biologically important compounds. secreted by the pineal gland. Besides, melatonin is involved in several physiological processes beyond the circadian rhythm [19,20]. Indole-3- is the most common and widely studied Serotonin (5-hydroxytryptamine) is an importantimportant neurotransmitter associated with the transmissionplant hormones of of nervenerve the impulses.impulses. class It(Figure It further further 2) [21].serves serves It isas as also a precursorprecurso the normalr to urinary melatonin,melatonin, tryptophan a neuro-hormoneneuro-hormone metabolite secretedobserved byby to the bethe pinealelevated pineal gland. ingland. patients Besides, Besides, wi melatoninth variousmelatonin is forms involved is involvedof in several disease in several physiological [22]. physiological processes processes beyond thebeyond circadian the circadian rhythm rhythm [19,20]. [19,20]. Indole-3-acetic Indole-3-acetic acid is acid the mostis the common most common and widely and widely studied studied plant 1.3. Significance of Indole Based Drugs hormonesplant hormones of the of auxin the auxin class class (Figure (Figure2)[ 212)]. [21]. It isIt is also also the the normal normal urinary urinary tryptophantryptophan metabolitemetabolite observedDelavirdine to be elevated is an inindole patients based withwith variousvariousanti-retroviral formsforms ofofdrug liverliver diseasediseaseapproved [[22].22 ].by the Food and Drug Administration (FDA) in 1997 for the treatment of HIV patients (Figure 3). The drug acts as a non- 1.3. Significance of Indole Based Drugs 1.3.nucleoside Significance reverse of Indole transcriptase Based Drugs inhibitor and an inhibitor of the cytochrome P450 enzyme CYP3A4 [23]. DelavirdineReserpine is is a an known indole indole based anti-retroviralalkaloid derived drug from approved the Rauwolfia by the Food serpentina and Drug plant. Administration It has been Delavirdine is an indole based anti-retroviral drug approved by the Food and Drug (FDA) in 1997 for the treatment of HIV patients (Figure3). The drug acts as a non-nucleoside reverse Administrationutilized as an (FDA)anti-psychotic in 1997 forand the anti-hypertensive treatment of HIV agentpatients to (Figure treat high3). The blood drug pressureacts as a non-[24]. transcriptase inhibitor and an inhibitor of the cytochrome P450 enzyme CYP3A4 [23]. nucleosidePanobinostat reverse is an transcriptaseoral histone deacetylaseinhibitor and inhibitor an inhibitor developed of the bycytochrome Novartis P450and approvedenzyme CYP3A4 to treat is a known indole derived from the Rauwolfia serpentina plant. It has been utilized as an [23].multiple Reserpine myeloma. is a Theknown drug indole is currently alkaloid in derived phase II from trials the to treatRauwolfia acute serpentina myeloid leukemiaplant. It has [25] been and anti-psychotic and anti-hypertensive agent to treat high blood pressure [24]. Panobinostat is an utilizedphase I andas IIan clinical anti-psychotic trials for theand treatment anti-hypertensive of AIDS [26]. agent Zafirlukast to treat is thehigh first blood orally pressure active indole- [24]. orallike leukotriene-receptor histone deacetylase inhibitorantagonist developed approved by by Novartis the FDA andto treat approved asthma to (Figure treat multiple 3) [27]. It myeloma. is mostly Panobinostat is an oral histone deacetylase inhibitor developed by Novartis and approved to treat The drug is currently in phase II trials to treat acute myeloid leukemia [25] and phase I and II clinical multiple myeloma. The drug is currently in phase II trials to treat acute myeloid leukemia [25] and trials for the treatment of AIDS [26]. Zafirlukast is the first orally active indole-like leukotriene-receptor phase I and II clinical trials for the treatment of AIDS [26]. Zafirlukast is the first orally active indole- like leukotriene-receptor antagonist approved by the FDA to treat asthma (Figure 3) [27]. It is mostly

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Molecules 2019, 24, x FOR PEER REVIEW 3 of 26 antagonist approved by the FDA to treat asthma (Figure3)[ 27]. It is mostly used in combination with used in combination with an inhaled steroid and/or long-acting bronchodilator. Tadalafil is another an inhaled steroid and/or long-acting bronchodilator. Tadalafil is another indole based drug approved indole based drug approved for the treatment of erectile dysfunction in men [28]. is an for the treatment of erectile dysfunction in men [28]. Pindolol is an antagonist of the serotonin 5-HT1A antagonist of the serotonin 5-HT1A receptor and it is used to treat and as an anti- receptor and it is used to treat hypertension and as an anti-depression agent [29,30]. Indomethacin is a depression agent [29,30]. Indomethacin is a non-steroidal anti-inflammatory drug applied to the non-steroidaltreatment of anti-inflammatory severe osteoarthritis, drug rheumatoid applied toarth theritis, treatment gouty arthritis, of severe and osteoarthritis, ankylosing spondylitis rheumatoid arthritis,[31] (Figure gouty 3). arthritis, and ankylosing spondylitis [31] (Figure3).

O H O H3C N SiH2 S O N H O O N N H H O N CH3 N H O OH O HN N .CH3SO3H N HN H H H O O CH3 O N O

Delavirdine Reserpine Panobinostat

O O Cl H N O OH O H H O N N O N HN S CH3 N O O O O O N N H O CH3 HN HO O O Zafirlukast Tadalafil Pindolol Indomethacin FigureFigure 3. 3.Indole Indole sca scaffoldffold in inFood Food andand DrugDrug Administration (FDA) (FDA) approved approved drugs. drugs.

1.4.1.4. Methodology Methodology for for Bibliographic Bibliographic Search Search WeWe used used the the following following databases databases to surveyto survey the the literature literature reporting reporting indole indole sca scaffoldffold usages usages for for lung cancerlung incancer in vitro in in and vitro in and vivo in models: vivo models: 1.1. Scifinder Scifinder website website at at https: https://scifinder.cas.org/.//scifinder.cas.org/. 2.2. PubMed PubMed website website at at https: https:////www.ncbi.nlm.nih.gov/pubmed/.www.ncbi.nlm.nih.gov/pubmed/. In Inaddition, addition, we wefiltered filtered the theavailable available articles articles based based on the on following the following criteria: criteria: a.a. Articles Articles must must have have chemical chemicalstructures structures ofof indoles. b.b. Articles Articles must must have have biology biology data data ofof indoles.indoles. c. Wec. We included included articles articles with with bioactivity bioactivity datadata ofof indolesindoles specifically specifically in in lung lung cancer. cancer. d.d. We We excluded excluded articles articles with with bioactivity bioactivity datadata ofof indoles other than than lung lung cancer. cancer.

2. Indole2. Indole Derivatives Derivatives as as Anti-Lung Anti-Lung CancerCancer AgentsAgents IndoleIndole based based alkaloids share share great great historical historical popularity popularity as anti-cancer as anti-cancer drugs. Thedrugs. most The prominent most amongprominent them among have been them , have been vincristine, , vinb vinflunine,lastine, vinflunine, and vinorelbine and vinorelbine derived derived from the from plant the plant roseus [32] (Figure 4). With over 150 alkaloids, C. roseus is the most well-studied [32] (Figure4). With over 150 alkaloids, C. roseus is the most well-studied medicinal medicinal plant. Vinorelbine is the most commonly used drug to treat lung cancer and vinblastine in plant. Vinorelbine is the most commonly used drug to treat lung cancer and vinblastine in combination combination with cisplatin is used in the treatment of NSCLC [33]. The anti-cancer activity of these with cisplatin is used in the treatment of NSCLC [33]. The anti-cancer activity of these derivatives derivatives was attributed to their ability to dissolve the mitotic spindles and cell division resulting was attributed to their ability to dissolve the mitotic spindles and cell division resulting from the from the microtubule disruption [33]. microtubule disruption [33].

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F OH N F N N N N N N N H H O O H N H H O O O O O O H H N O N O O O R OH H3C O OH O O O N O O O O OH R=CH3 Vinblastin Vinorelbine Vinflunine O R = CHO Vincristine

O N O N H N N NH N N N F H N O

N N O NH NH O O N N H Alectinib Osimertinib Sunitinib

O H H N N HO O N O CO2CH3 O F NH N H H H CHO O N R1 R2 NH2 N N N Vallesiachotamine: R =H;R =CH 1 2 3 Anlotinib Nintedanib O Iso-vallesiachotamine: R1 =CH3;R2 =H Figure 4.4. Indole containing anti-lung cancer drugsdrugs inin clinicalclinical andand pre-clinicalpre-clinical stages.stages.

AlectinibAlectinib isis aa popularpopular indoleindole basedbased oraloral drugdrug developeddeveloped byby AstraZeneca.AstraZeneca. FDAFDA approvedapproved thethe drugdrug inin 20152015 forfor thethe treatmenttreatment ofof crizotinib-resistantcrizotinib-resistant NSCLCNSCLC [34[34].]. Sunitinib is aa multi-targetedmulti-targeted receptorreceptor tyrosine kinase kinase inhibitor inhibitor that that was was approved approved in inthe the first-line first-line treatment treatment of advanced of advanced renal renal cell cellcarcinoma carcinoma and and gastrointestinal gastrointestinal stromal stromal tumors tumors [35] [.35 Osimertinib]. Osimertinib was was also also approved approved by bythe the FDA FDA in in2015 2015 to totreat treat metastatic metastatic EGFRT790M EGFRT790M mutation-p mutation-positiveositive NSCLC NSCLC patients [[36].36]. Osimertinib andand sunitinibsunitinib areare thethe indoleindole basedbased drugs,drugs, marketedmarketed forfor thethe treatmenttreatment ofof NSCLC,NSCLC, advancedadvanced renalrenal cellcell carcinoma,carcinoma, andand gastrointestinalgastrointestinal stromalstromal tumors,tumors, respectivelyrespectively [[36]36] (Figure(Figure4 ).4). Mishra Mishra et et al. al. recentlyrecently isolatedisolated sevenseven indole-basedindole-based alkaloidsalkaloids andand studiedstudied thethe anti-proliferativeanti-proliferative activitiesactivities ofof theirtheir isolatedisolated compounds.compounds. They They observed observed that that aglycone aglycone indole indole based based alkaloids, alkaloids, namely namely vallesiachotamine vallesiachotamine and andiso- iso-vallesiachotamine,vallesiachotamine, exhibit exhibit anti-tumor anti-tumor activity activity wi withth The The half half maximal maximal inhibitory inhibitory concentration (IC(IC5050) valuesvalues ofof 4.244.24 µμMM andand 3.793.79 µμM,M, respectively,respectively, againstagainst H1299H1299 humanhuman lung cancer cells (Figure 44))[ [37].37]. AnlotinibAnlotinib isis aa novelnovel oraloral multi-targetmulti-target tyrosinetyrosine kinasekinase inhibitor,inhibitor, usedused forfor thethe third-linethird-line treatmenttreatment ofof advancedadvanced lunglung cancercancer [[38].38]. TheThe potencypotency ofof indoles indoles as as anti-cancer anti-cancer agents agents is is exemplified exemplified by by (i) (i) various various indole indole derivatives, derivatives, such such as indole-3-carbinol,as indole-3-carbinol, indole-3-carboxaldehyde; indole-3-carboxaldehyde; (ii) functionalized (ii) functionalized indoles, indoles, such as such diaryl-indoles, as diaryl-indoles, indolyl chalcones,indolyl chalcones, indolyl azoles, indolyl and azoles, (iii) bisindole and (iii) derivativesbisindole derivatives [39]. Several [39]. studies Several cast studies light on cast the light anti-cancer on the eanti-cancerfficacy of indole efficacy derivatives of indole [40 derivatives–43]. Besides, [40–43]. several Besides, reviews several were submittedreviews were in recent submitted years exploring in recent theyears biological exploring and the pharmacological biological and pharmacological applications of indole applications derivatives of indole as anticancer derivatives agents as [anticancer39,44–47]. Thoughagents [39,44–47]. many comprehensive Though many reviews comprehensive were published, reviews focusing were on indolepublished, derivatives focusing as anti-canceron indole agents,derivatives so far as to anti-cancer our knowledge, agents, there so arefar noto our reports knowledge, specifically there focused are no on reports the effi cacyspecifically of indole-based focused compoundson the efficacy in combattingof indole-based lung compounds cancer. Therefore, in comb weatting are seeking lung cancer. to fill thisTherefore, gap by presentingwe are seeking a brief to reviewfill this focusedgap by presenting on the development a brief review of indole-based focused on the derivatives development as anti-lung of indole-based cancer agents. derivatives In this as paper,anti-lung we cancer included agents. work In between this paper, 2000 we and includ 2019,ed ofwork indole-based between 2000 derivatives and 2019, in theof indole-based clinical and subclinicalderivatives stages in the ofclinical development and subclinical to combat stages lung of cancer. development As it is not to possiblecombat lung to include cancer. the As synthesis it is not ofpossible all indole to include based anti-lung the synthesis cancer of agents, all indole we arebase reportingd anti-lung herein cancer the synthesisagents, we of are some reporting of the selected herein the synthesis of some of the selected derivatives. We apologize in advance for possible neglect of any relevant work including synthesis on the subject. Basic mechanisms by which indole derivatives

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Molecules 2019, 24, x FOR PEER REVIEW 5 of 26 derivatives. We apologize in advance for possible neglect of any relevant work including synthesis on theexhibit subject. anti-lung Basic cancer mechanisms properties by which involve indole the indu derivativesction of exhibitapoptosis, anti-lung microt cancerubule inhibition, properties involveprotein thekinase induction inhibition, of apoptosis,histone deacetylase microtubule inhibition, inhibition, and DNA protein topoisomerase kinase inhibition, inhibition histone (Figure deacetylase 5). In the inhibition,following sections, and DNA we topoisomerase will discuss several inhibition derivati (Figureves of5 ).indoles, In the followingdeveloped sections, and understudy we will for discuss their severalprospective derivatives use against of indoles, lung cancer, developed along and with understudy their mechanism for their and prospective synthesis use of some against of the lung selected cancer, alongderivatives. with their mechanism and synthesis of some of the selected derivatives.

DNA R Topoisomerase R HDAC Inhibition Inhibtion N H/R

Tubulin Protein Kinase Inhibition Inhibition Figure 5. Basic mechanism of action for indole containing anti-lung cancer drugs. Figure 5. Basic mechanism of action for indole containing anti-lung cancer drugs.

2.1. Indole Derivatives as Kinase Inhibitors Protein tyrosine kinases are a large multi-gene family comprising key signaling molecules and, therefore, are attractive drug drug targets. targets. There There are are two two types types of of tyrosine tyrosine kinases: kinases: a) (a)receptor receptor kinases, kinases, b) (b)non-receptor non-receptor kinases. kinases. Receptor Receptor kinases kinases comprising comprising transmembrane, transmembrane, an extracellular an extracellular domain, domain, and an andintracellular an intracellular domain. domain. Non-receptor Non-receptor kinases kinases comprise comprise only only an anintracellular intracellular domain domain with with no extracellular or or transmembrane. transmembrane. Both Both kinases kinases play play crit criticalical roles roles in cellular in cellular signaling, signaling, cell cellgrowth, growth, cell celldivision, division, cellular cellular , metabolism, and and apoptosis. apoptosis. Studies Studies have have confirmed confirmed that that any any kind kind of of upregulation upregulation or overexpression ofof thethe receptors,receptors, or or any any mutation mutation in in these these receptors, receptors, can can lead lead to lungto lung cancer cancer [48 –[48–50]. Therefore,50]. Therefore, indole indole based based small small molecule molecule inhibitors inhibitors targeting targeting the the kinase kinase receptors receptors havehave becomebecome a promising option forfor drugdrug discoverydiscovery scientistsscientists inin theirtheir attemptattempt toto battlebattle lunglung cancer.cancer.

2.2. Targeting Akt Signaling Pathway Nearly 51% of the NSCLC patient samples and 74% of the NSCLC cell lines show activation of phosphatidylinositol 3-kinase3-kinase/Akt/mTOR/Akt/mTOR pathway pathway [51 [51,52].,52]. Protein Protein kinase kinase B/Akt B/Akt regulates regulates several several key cellularkey cellular processes processes such assuch cell as division, cell division, cell proliferation, cell proliferation, angiogenesis, angiogenesis, and cell and survival. cell survival. It activates It signalingactivates signaling pathways pathways downstream downstream of tyrosine of kinases tyrosine and kinases dysregulation and dysregulation of these signaling of these pathwayssignaling haspathways been observed has been in severalobserved human in several cancers. human Because ca ofncers. the biologicalBecause rolesof the of Aktbiological signaling roles pathways, of Akt severalsignaling categories pathways, of inhibitorsseveral categories targeting theseof inhibi kinasestors weretargeting developed these forkina NSCLCses were treatment developed [53,54 for]. NSCLCNesi treatment et al. designed [53,54]. and synthesized a novel set of 2--derivatives ((6a–c), (OXIDs)) targetingNesi serineet al. /designedthreonine and kinases, synthesized 3-phosphoinositide-dependent a novel set of 2-oxindole-derivatives protein kinase-1 ((6a–c and), (OXIDs))/or Akt pathwaystargeting [/threonine55]. They revealed kinase the significances, 3-phosphoinositide-dependent of the oxindole core along protein with the thiophenekinase-1 and/or , Akt inpathways the 3rd position[55]. They in exerting revealed the the antitumor significance activity. of Inthe their oxindole studies, core they along found with that thethe compounds 6a-csubstituent,showed in six-fold the 3rd higherposition antitumor in exerting activity the antitumor than Akt activi inhibitorty. In perifosinetheir studies, and they were found more that potent the thancompounds sunitinib 6a-c with showed 2.5 to 10-foldsix-fold higher higher anti-cancer antitumor activity.activity ICthan50 values Akt inhibitor ranged fromperifosine submicromolar and were tomore micromolar. potent than These sunitinib studies with revealed 2.5 to the10-fold potential higher of anti-cancer oxindole core activity. in the IC further50 values development ranged from of futuresubmicromolar therapeutic to agentsmicromolar. to treat These NSCLC studies [55]. revealed the potential of oxindole core in the further developmentThe synthesis of future of OXIDs therapeuti is depictedc agents in to Scheme treat NSCLC1[ 55]. [55]. Briefly, compound 2 (5-amino-2-oxindole) was synthesizedThe synthesis by of the OXIDs Palladium is depicted on in Scheme (Pd/C) catalyzed1 [55]. Briefly, hydrogenation compound of 2 compound (5-amino-2-oxindole)1, followed bywas condensation synthesized withby the the 2-chloro-acetylchloridePalladium on carbon (Pd/C) resulting catalyzed in compound hydrogenation3. The subsequent of compound reaction 1, offollowed intermediate by condensation3 with compound with the 2-chloro-acetylchloride4 in the presence of resulting carbonatein compound afforded 3. The derivative subsequent5, followedreaction byof theintermediate Knoevenagel 3 with reaction compound involving 4 the in corresponding the presence heterocyclesof potassium resulting carbonate in the afforded desired OXIDsderivative compounds 5, followed (6a–c by). the Knoevenagel reaction involving the corresponding heterocycles resulting in the desired OXIDs compounds (6a–c).

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SchemeScheme 1.1. SynthesisSynthesis ofof 2-oxindole-derivatives2-oxindole-derivatives (OXIDs)(OXIDs) ((6a–c6a–c)6a–c)) adaptedadapted fromfrom the thethe reference referencereference [ [55].55[55].]. 2.3. Epidermal Growth Factor (EGFR) Inhibition 2.3.2.3. EpidermalEpidermal GrowthGrowth FactorFactor (EGFR)(EGFR) InhibitionInhibition Osimertinib (AZD9291, 16a) is an FDA-approved drug to treat non-small lung cancer as an EGFR OsimertinibOsimertinib (AZD9291, (AZD9291, 16a 16a)) is is an an FDA-approved FDA-approved drug drug to to treat treat non-small non-small lung lung cancer cancer as as an an EGFR EGFR inhibitor [36]. However, AZD9291 showed low specificity to EGFR along with severe side effects inhibitorinhibitor [36].[36]. However,However, AZD9291AZD9291 showedshowed lowlow specificspecificityity toto EGFREGFR alongalong withwith severesevere sideside effectseffects andand and cardiotoxicity at high doses (Scheme2). A structure-activity relationship study of AZD9291 cardiotoxicitycardiotoxicity atat highhigh dosesdoses (Sch(Schemeeme 2).2). AA structure-activitystructure-activity relatirelationshiponship studystudy ofof AZD9291AZD9291 reportedreported reported by Zhao et al. showed that the fluorinated analog (17, Figure6) improved selectivity towards byby ZhaoZhao etet al.al. showedshowed thatthat thethe fluorinatedfluorinated analoganalog ((1717,, FigureFigure 6)6) improvedimproved selectivityselectivity towardstowards 790M/L858R EGFRTEGFRT790M/L858R doubledouble mutants mutants with with IC IC5050 asas low low as as 8 8 nM nM and a 200-fold200-fold increaseincrease inin thethe selectivityselectivity EGFRT790M/L858R double mutants with IC50 as low as 8 nM and a 200-fold increase in the selectivity towards wild type EGFR. It was theorized that the fluorinated indole (17) plays an important role towardstowards wildwild typetype EGFR.EGFR. ItIt waswas theorizedtheorized thatthat thethe fluorinatedfluorinated indoleindole ((1717)) playsplays anan importantimportant rolerole inin in enhancing the binding interaction with T790M active binding domain of EGFR and reducing the enhancingenhancing thethe bindingbinding interactioninteraction withwith T790MT790M actiactiveve bindingbinding domaindomain ofof EGFREGFR andand reducingreducing thethe demethylation ability of the indole ring, which in turn, can enhance the anti-metabolism ability of demethylationdemethylation abilityability ofof thethe indoleindole ring,ring, whichwhich inin turn,turn, cancan enhanceenhance thethe anti-metabolismanti-metabolism abilityability ofof AZD9291 derivatives. The fluorinated derivative of AZD9291 (17), however, resulted in the loss of AZD9291AZD9291 derivatives.derivatives. TheThe fluorinatedfluorinated derivativederivative ofof AZD9291AZD9291 ((1717),), however,however, resultedresulted inin thethe lossloss ofof kinase activity. Next, the authors designed compound 16b by the aid of molecular docking studies kinasekinase activity.activity. Next,Next, thethe authorsauthors designeddesigned compoundcompound 16b16b byby thethe aidaid ofof molecularmolecular dockingdocking studiesstudies toto to obtain an optimized derivative without fluorine substitution. They showed that 16b can serve obtainobtain anan optimizedoptimized derivativederivative withoutwithout flfluorineuorine substitution.substitution. TheyThey showedshowed thatthat 16b16b cancan serveserve asas aa as a potent EGFRT790M/L858R790M/L858R inhibitor [56]. The synthesis of compounds 16a and 16b is shown in potentpotent EGFRTEGFRT790M/L858R inhibitorinhibitor [56].[56]. TheThe synthesissynthesis ofof compoundscompounds 16a16a andand 16b16b isis shownshown inin SchemeScheme 22 Scheme2[56,57]. [56,57].[56,57].

Scheme 2. Synthesis of compounds 16a and 16b adapted from the references [56,57]. SchemeScheme 2.2. SynthesisSynthesis ofof compoundscompounds 16a16a andand 16b16b adaptedadapted fromfrom thethe referencesreferences [56][56] andand [57].[57]. The first step of the synthesis involved the of indole (7) using methyl iodide and TheThe firstfirst stepstep ofof thethe synthesissynthesis involvedinvolved thethe methylationmethylation ofof indoleindole ((77)) usingusing methylmethyl iodideiodide andand hydride to furnish the methylated indole (8). A mixture of the 2,4-dichloro- (9a) sodiumsodium hydridehydride toto furnishfurnish thethe methylatedmethylated indoleindole ((88).). AA mixturemixture ofof thethe 2,4-dichloro-pyrimidine2,4-dichloro-pyrimidine ((9a9a)) oror 2,4-dichloro-6-methyl-pyrimidine2,4-dichloro-6-methyl-pyrimidine ((9b9b)) inin dimethoxyethanedimethoxyethane andand AlClAlCl33 withwith 1-methylindole1-methylindole ((88)) or 2,4-dichloro-6-methyl-pyrimidine (9b) in dimethoxyethane and AlCl3 with 1-methylindole (8) yielded compound 10a or 10b respectively. A nucleophilic aromatic substitution reaction between yieldedyielded compoundcompound 10a10a oror 10b10b respectively.respectively. AA nucleophilicnucleophilic aromaticaromatic substitutionsubstitution reactionreaction betweenbetween the amino compound 11 and the chloro pyrimidine 10a/10b in generated the fluoro intermediate thethe aminoamino compoundcompound 1111 andand thethe chlorochloro pyrimidinepyrimidine 10a/10b10a/10b inin generatedgenerated thethe fluorofluoro intermediateintermediate (12a/12b). The reaction of the fluoro compounds (12a/12b) with N,N,N-trimethylethane-l,2-diamine ((12a/12b12a/12b).). TheThe reactionreaction ofof thethe fluorofluoro compoundscompounds ((12a/12b)12a/12b) withwith N,N,N-trimethylethane-l,2-diamineN,N,N-trimethylethane-l,2-diamine inin diisopropylethylaminediisopropylethylamine andand dimethylacetamidedimethylacetamide gavegave thethe nitronitro intermediatesintermediates 13a/13b,13a/13b, whichwhich waswas

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MoleculesMolecules 2019, 201924, x, FOR24, x PEERFOR PEER REVIEW REVIEW 7 of 267 of 26 in diisopropylethylamine and dimethylacetamide gave the nitro intermediates 13a/13b, which was subsequentlysubsequently reduced reducedreduced to the toto theaminesthe amines 14a/14b14a 14a/14b/14b. The.. The Thelatter latter latter amines amines amines were were were treated treated treated with with with acryloyl acryloyl acryloyl chloride chloride chloride to to affordatoff ordafford the the desiredthe desired desired final final final products products products (16a (16a /(16b16a/16b/)16b )(Scheme (Scheme) (Scheme 2).2). 2).

FigureFigure 6. Structures 6. Structures of compounds of compounds 17 and 17 AZD3463and AZD3463. . 2.4. Anaplastic Lymphoma Kinase Inhibition 2.4. Anaplastic2.4. Anaplastic Lymphoma Lymphoma Kinase Kinase Inhibition Inhibition Anaplastic lymphoma kinase (ALK) belongs to the family of tyrosine kinases and is regarded as a AnaplasticAnaplastic lymphoma lymphoma kinase kinase (ALK) (ALK) belongs belongs to the to family the family of tyrosine of tyrosine kinases kinases and andis regarded is regarded as as potential target for the treatment of neuroblastomas as ALK gene mutations and overexpression is a potentiala potential target target for the for treatmentthe treatment of neuroblastom of neuroblastomas asas ALK as ALK gene gene mutation mutations ands andoverexpression overexpression is is frequently observed in neuroblastoma patients. AZD3463 is an ALK inhibitor designed by Astrazeneca frequentlyfrequently observed observed in neuroblastomain neuroblastoma patients. patients. AZD3463 AZD3463 is anis ALKan ALK inhibitor inhibitor designed designed by by to overcome the acquired resistance towards crizotinib (Figure6). Crizotinib is an FDA-approved drug AstrazenecaAstrazeneca to overcome to overcome the acquiredthe acquired resistance resistance towards towards crizotinib crizotinib (Figure (Figure 6). Crizotinib 6). Crizotinib is an is FDA- an FDA- for the treatment of NSCLC [58]. It is further known to be a potent second-generation ALK (anaplastic approvedapproved drug drug for the for treatment the treatment of NSCLC of NSCLC [58]. [58]. It is furtherIt is further known known to be to a bepotent a potent second-generation second-generation lymphoma kinase) inhibitor, which proved effective against a broad spectrum of ALK rearrangements ALKALK (anaplastic (anaplastic lymphoma lymphoma kinase) kinase) inhibitor, inhibitor, which which proved proved effective effective against against a broad a broad spectrum spectrum of of and ALK mutations [59]. ALKALK rearrangements rearrangements and andALK ALK mutations mutations [59]. [59]. Alectinib, as mentioned earlier, is an FDA approved drug for the treatment of NSCLC (Scheme3). Alectinib,Alectinib, as mentioned as mentioned earlier, earlier, is an is FDA an FDA approved approved drug drug for the for treatmentthe treatment of NSCLC of NSCLC (Scheme (Scheme It is a highly selective and potent ALK inhibitor. Synthesis of alectinib was accomplished in eight steps, 3). It3). is Ita highlyis a highly selective selective and andpotent potent ALK ALK inhibitor. inhibitor. Synthesis Synthesis of alectinib of alectinib was wasaccomplished accomplished in eight in eight as shown in Scheme3[60,61]. steps,steps, as shown as shown in Scheme in Scheme 3 [60,61]. 3 [60,61].

NHNH 2NHNH2

NC H NBS, ACN NC H H DDQ, THF/HDDQ,2 THF/HO O H OMe NBS, ACN N OMe OMe 2 N N OMe O O OMe OMe O O OMe OMe N rt rt 0°C 0°C TFA, 100TFA, °C 100 °C Br Br Br 92% yield Br Br 17% yield17% yieldN N 92% yield Br O NC in two stepsin two steps O 1818 19 19NC 20 20 21 21 O O N N N N PyridiniumPyridinium H Trifluoromethanesulfonic H H H H H OH TrifluoromethanesulfonicN OTf OTf N N N hydrochloridehydrochloride N N anhydrideOH anhydride N 4-Morpholinopiperidine4-Morpholinopiperidine N , rt; NMP, 120 °C 190 °C 190 °C Br pyridine, rt; Br Br NMP, 120 °C Br Br Br N N N N 54% yield N N 64% yieldO 98% yield O 54% yield O O 64% yieldO 98% yield O 2222 23 23 24 24

O O O O A) TIPS-acetylene N N N N A) TIPS-acetylene N N 10%, Pd/C, H N N Pd(CH CN) Cl , H 10%, Pd/C,2 H2 H 3Pd(CH2 32CN)2Cl2, H N H N N N N N N N X-Phos, Cs CO , X-Phos,2 3 Cs2CO3, THF/MeOH,THF/MeOH, rt rt CH3CN,CH 80CN, °C, 80 °C, 3 25% yield B) TBAF, THF N N 25% yieldN N B) TBAF, THF O O O O rt rt 56% yield56% yield 25 25 AlectinibAlectinib Scheme 3. Synthesis of alectinib adapted from the references [60,61]. SchemeScheme 3. Synthesis 3. Synthesis of alectinib of alectinib adapted adapted from from the references the references [60] and[60] [61].and [61]. The bromination of compound 18 with N-bromosuccinimide, followed by the ,The Thebromination bromination resulted of in compound theof compound regioisomeric 18 with 18 with mixtureN-bromosuccinimide, N-bromosuccinimide, (1:1, 1-CN- and followed 3-CN-derivatives) followed by theby Fischerthe Fischer of compoundindole indole synthesis,20synthesis,. The resulted desired resulted in the isomer in regioisomericthe regioisomeric was isolated mixtur andmixture (1:1, thee (1:1, 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone1-CN- 1-CN- and and3-CN-derivatives) 3-CN-derivatives) of compound of compound 20 (DDQ). 20. The oxidationThedesired desired wasisomer conducted,isomer was wasisolated resulting isolated and in theandthe ketone the2,3- Dichloro-5,6-dicyano-1,4-benzoquinone212,3-. DemethylationDichloro-5,6-dicyano-1,4-benzoquinone of compound 21 with pyridinium(DDQ) (DDQ) oxidationhydrochlorideoxidation was wasconducted, conducted, generated resulting the resulting in the in ( 22ketone the). Theketone 21. resulting Demethylation 21. Demethylation alcohol ( 22of )compound was of compound then triflated 21 with 21 with andpyridinium thenpyridinium reacted hydrochloridewithhydrochloride 4-morpholinopiperidine generated generated the alcoholthe toalcohol provide (22). ( 22The the). The bromoresulting resulting compound alcohol alcohol ((2422)). (was The22) was bromothen then triflated intermediate triflated and andthen (24 )then was reactedthenreacted with subjected with 4-morpholinopiperidine 4-morpholinopiperidine to Sonogashira coupling to provide to provide with the acetylene, bromo the bromo compound followed compound by(24) hydrogenation .( The24). Thebromo bromo intermediate of intermediate the terminal (24) alkyne(was24) wasthen generated then subjected subjected the to desired Sonogashira to Sonogashira compound coupling coupling (alectinib), with with acetylene, as shownacetylene, followed in Scheme followed by3. hydrogenation by hydrogenation of the of the terminalterminal alkyne alkyne generated generated the desiredthe desired compound compound (alectinib), (alectinib), as shown as shown in Scheme in Scheme 3. 3.

2.5. Protein2.5. Protein Kinase Kinase C Inhibition C Inhibition

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ProteinProtein kinasekinase CC (PKC)(PKC) isis aa familyfamily ofof structurallystructurally relatedrelated serine-threonineserine-threonine kinaseskinases thatthat cancan bebe activatedactivated byby G-proteinG-protein coupledcoupled receptorsreceptors [[62].62]. PKCPKC isis implicated inin several cellularcellular functionsfunctions andand thethe regulationregulation ofof survivalsurvival signalssignals in variousvarious cell typestypes and, therefore, PKC has become a drug targettarget forfor thethe developmentdevelopment ofof anti-canceranti-cancer drugs.drugs. The activationactivation of PKC by various oncogenes can lead toto thethe malignantmalignant transformation and abnormal expression of PKC isoforms, as detected in the head, neck, andand otherother typestypes ofof cancers.cancers. EnzastaurinEnzastaurin isis aa popularpopular anti-tumor anti-tumor agent, agent, which which showed showed promising promising results results with with T-cell T-cell and and B-cell B- lymphoma,cell lymphoma, multiple multiple myeloma myeloma and other and other tumorsolid tumor malignancies malignancies (Scheme (Scheme4). Enzastaurin 4). Enzastaurin is a potent is a inhibitorpotent inhibitor of PKC of and PKC PI3K and/AKT PI3K/AKT pathway. pathway. It is found It is to found effectively to effectively inhibit tumorinhibit cell tumor growth cell ingrowth both inin vitroboth andin vitro mouse and xenograft mouse xenograft models [ 63models]. Nakajima [63]. Nakajima and his team and showedhis team that showed enzastaurin that enzastaurin displayed celldisplayed growth cell inhibition growth withinhibition IC50 of with 3–10 ICµmol50 of/ L,3–10 as exhibitedμmol/L, as in exhibited a panel of in both a panel SCLC of andboth NSCLC SCLC and cell linesNSCLC [64 ,65cell]. Besides,lines [64,65]. they found Besides, that enzastaurinthey found canthat suppress enzastaurin tumor-induced can suppress angiogenesis tumor-induced in A549 NSCLCangiogenesis xenografts in A549 [66 ].NSCLC The drug xenografts is undergoing [66]. The clinical drug trials is undergoing to evaluate clinical its efficacy trials in to the evaluate treatment its ofefficacy NSCLC in andthe treatment several other of NSCLC types of and cancers several [67 other]. types of cancers [67].

Scheme 4. Synthesis of enzastaurin adapted from the reference [65]. Scheme 4. Synthesis of enzastaurin adapted from the reference [65]. The synthesis of enzastaurin is shown in Scheme 4 [65]. Briefly, the reduction of indole-3- The synthesis of enzastaurin is shown in Scheme4[ 65]. Briefly, the reduction of indole-3-acetamide acetamide (26) with BH3.pyridine gave the indolin-3-acetamide (27) followed by reductive amination (with26) with the BHketone3.pyridine (28) resulted gave the in indolin-3-acetamidethe intermediate 29. ( 27Compound) followed 30 by was reductive obtained amination by oxidation with the of ketonecompound (28) resulted29 using inDDQ. the intermediateOn the other 29hand,. Compound the indole-3-glyoxylate30 was obtained ester by oxidation(32) was synthesized of compound from29 using1-methylindole DDQ. On the(31 other) and hand,oxalyl the chloride. indole-3-glyoxylate Finally, conden estersation (32) wasof the synthesized amide intermediate from 1-methylindole (30) with (indole-3-glyoxylate31) and oxalyl chloride. ester Finally, (32) in condensationthe presence of of a the amide gene intermediaterated enzastaurin (30) with [67] indole-3-glyoxylate (Scheme 4). ester (32) in the presence of a base generated enzastaurin [67] (Scheme4). 2.6. GSK Inhibition 2.6. GSK Inhibition Tivantinib is an oral, selective indole based small molecule MET inhibitor, being evaluated in Tivantinib is an oral, selective indole based small molecule MET inhibitor, being evaluated in advanced clinical trials for the treatment of NSCLC (Scheme 5). Early reports showed that tivantinib advanced clinical trials for the treatment of NSCLC (Scheme5). Early reports showed that tivantinib is a is a potent and highly selective inhibitor of receptor tyrosine kinase (cMET). However, further potent and highly selective inhibitor of receptor tyrosine kinase (cMET). However, further investigation investigation led by Rix et al. revealed glycogen synthetase kinase (GSK)3α and GSK3β to be novel led by Rix et al. revealed glycogen synthetase kinase (GSK)3α and GSK3β to be novel tivantinib tivantinib targets. In their detailed study of mechanism, they found that tivantinib acts by the targets. In their detailed study of mechanism, they found that tivantinib acts by the simultaneous simultaneous inhibition of GSK3α and GSK3β leading to apoptosis in lung cancer cells [68]. Their inhibition of GSK3α and GSK3β leading to apoptosis in lung cancer cells [68]. Their experiments experiments demonstrated that (−)-tivantinib was more potent than (+)-tivantinib in the inhibition of demonstrated that ( )-tivantinib was more potent than (+)-tivantinib in the inhibition of GSK3α GSK3α and GSK3β.− The latest investigation by Scagliotti et al. has shown that a combination of and GSK3β. The latest investigation by Scagliotti et al. has shown that a combination of tivantinib tivantinib and erlotinib can enhance treatment efficacy in patients with previously treated, EGFR and erlotinib can enhance treatment efficacy in patients with previously treated, EGFR mutant, mutant, non-squamous NSCLC, as compared to erlotinib alone [69]. non-squamous NSCLC, as compared to erlotinib alone [69].

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SchemeScheme 5. Synthesis 5. Synthesis of oftivantinib tivantinib adapted adapted from from the the references references [69] [69 and,70]. [70].

TheThe synthesissynthesis ofof tivantinibtivantinib isis shownshown inin SchemeScheme5 [5 [69,70].69,70]. TheThe reactionreaction ofof thethe tetrahydroquinolinetetrahydroquinoline ((3333)) withwith thethe bromo-ethylpyruvatebromo-ethylpyruvate yieldedyielded thethe ketoesterketoester 3434,, whichwhich waswas transformedtransformed toto thethe esterester indoleindole 3535under under anhydrousanhydrous magnesiummagnesium chloridechloride treatment.treatment. EsterEster 3535 waswas hydrolyzedhydrolyzed toto carboxyliccarboxylic acidacid intermediateintermediate 3636 followedfollowed byby decarboxylationdecarboxylation reactionreaction usingusing coppercopper chromitechromite andand quinolinequinoline aaffordedfforded thethe indoleindole37 37,, which which was was treated treated with with oxalyl oxalyl chloride chloride and and methanol methanol toto obtainobtain thethe ketoesterketoester 3838.. CondensationCondensation of the ketoester 38 andand indole-3-acetamide indole-3-acetamide ( (2626)) generated generated the the intermediate intermediate 3939 asas a aracemic racemic mixture mixture of of tivantinib. tivantinib. Preparative Preparative chiral chiral HPLC HPLC purification purification yiel yieldedded two opticallyoptically purepure diastereoisomers of (3R, 4R) ( )-tivantinib and (3S, 4S) (+)-tivantinib (Scheme5). diastereoisomers of (3R, 4R) −(−)-tivantinib and (3S, 4S) (+)-tivantinib (Scheme 5). 2.7. Inhibition of Multiple Receptor Kinases 2.7. Inhibition of Multiple Receptor Kinases Anlotinib is a novel inhibitor targeting multiple receptor tyrosine kinases, namely vascular Anlotinib is a novel inhibitor targeting multiple receptor tyrosine kinases, namely vascular endothelial growth factor receptor type 2 and 3 (VEGF 2 and 3), the platelet-derived growth factor b endothelial growth factor receptor type 2 and 3 (VEGF 2 and 3), the platelet-derived growth factor b (PDGFb), and the fibroblast growth factor 2 (FGF-2) [71] (Figure4). Studies revealed that VEGF is a (PDGFb), and the fibroblast growth factor 2 (FGF-2) [71] (Figure 4). Studies revealed that VEGF is a critical growth factor in tumor angiogenesis. Along with PDGF and FGF-2, it stimulates proliferation, critical growth factor in tumor angiogenesis. Along with PDGF and FGF-2, it stimulates proliferation, migration, survival, and new vessel formation of endothelial cells in tumors. Studies showed that migration, survival, and new vessel formation of endothelial cells in tumors. Studies showed that inhibition of these angiogenic receptor tyrosine kinases can be very effective in the treatment of tumors. inhibition of these angiogenic receptor tyrosine kinases can be very effective in the treatment of Notably, the inhibitory effect of anlotinib was much more pronounced than with sunitinib, sorafenib, tumors. Notably, the inhibitory effect of anlotinib was much more pronounced than with sunitinib, and nintedanib suggesting it as a potent anti-lung cancer drug. Anlotinib has emerged as a potential sorafenib, and nintedanib suggesting it as a potent anti-lung cancer drug. Anlotinib has emerged as third-line treatment in advanced NSCLC patients [72]. a potential third-line treatment in advanced NSCLC patients [72]. Nintedanib is an oral, small molecule multiple kinase inhibitor (Figure4). This drug in combination Nintedanib is an oral, small molecule multiple kinase inhibitor (Figure 4). This drug in with docetaxel was approved worldwide for the treatment of NSCLC [73]. It functions as a tyrosine combination with docetaxel was approved worldwide for the treatment of NSCLC [73]. It functions kinase inhibitor targeting three angiokinase inhibitors including VEGF (1–3), PDGF receptors (α/β) as a tyrosine kinase inhibitor targeting three angiokinase inhibitors including VEGF (1–3), PDGF and fibroblast growth factors (1–3). Both in vitro and in vivo studies in human NSCLC xenografts receptors (α/β) and fibroblast growth factors (1–3). Both in vitro and in vivo studies in human NSCLC have confirmed that by the inhibition of both AKT and mitogen-activated protein kinases signaling xenografts have confirmed that by the inhibition of both AKT and mitogen-activated protein kinases pathways, nintedanib resulted in the inhibition of cell proliferation, apoptosis in endothelial cells, and signaling pathways, nintedanib resulted in the inhibition of cell proliferation, apoptosis in endothelial the cell types involved in angiogenesis [74]. cells, and the cell types involved in angiogenesis [74]. 2.8. Tubulin Inhibition 2.8. Tubulin Inhibition Tubulin is a globular protein comprising α and β-heterodimers, which polymerize to form the Tubulin is a globular protein comprising α and β-heterodimers, which polymerize to form the biopolymers of microtubules. Being the third major component of the cytoskeleton, microtubules biopolymers of microtubules. Being the third major component of the cytoskeleton, microtubules play a critical role in cell division, in addition to aiding in both inter and intra-cellular movement and play a critical role in cell division, in addition to aiding in both inter and intra-cellular movement and maintaining cell shape [75]. As microtubules play a key role in cell division, they are attractive targets maintaining cell shape [75]. As microtubules play a key role in cell division, they are attractive targets for the development of anti-cancer agents. for the development of anti-cancer agents. Tubulin inhibitors interfere with the polymerization and depolymerization of the microtubules. Tubulin inhibitors interfere with the polymerization and depolymerization of the microtubules. They are categorized as either tubulin stabilizing agents or destabilizing agents (Figure7). While the They are categorized as either tubulin stabilizing agents or destabilizing agents (Figure 7). While the tubulin stabilizing agents ultimately lead to the polymerization of microtubules by inhibiting tubulin stabilizing agents ultimately lead to the polymerization of microtubules by inhibiting depolymerization, the destabilizing agents function by inhibiting polymerization, thereby shortening

Molecules 2020, 25, 1615 10 of 25 MoleculesMolecules 20192019,, 2424,, xx FORFOR PEERPEER REVIEWREVIEW 1010 ofof 2626 depolymerization,thethe microtubulesmicrotubules the[76].[76]. destabilizing TheThe indoleindole agents basedbased function alkaloidalkaloid byss inhibiting andand theirtheir polymerization, derivatives,derivatives, suchsuch thereby asas shorteningvincristine,vincristine, thevinblastine,vinblastine, microtubules vinorelbine,vinorelbine, [76]. The vinflunine,vinflunine, indole based vindesinevindesine alkaloids belongbelong and their toto derivatives,thethe classclass ofof suchpolymerizationpolymerization as vincristine, inhibitorsinhibitors vinblastine, thatthat vinorelbine,bindbind toto thethe ββ vinflunine,-subunit-subunit ofof tubulin vindesinetubulin atat aa belong distinctdistinct to regionregion the class calledcalled of as polymerizationas thethe vinca-bindingvinca-binding inhibitors site,site, asas that shownshown bind inin FiguretoFigure the β 77-subunit [76].[76]. of tubulin at a distinct region called as the vinca-binding site, as shown in Figure7[76].

FigureFigureFigure 7. 7.7. Binding BindingBinding sites sitessites in inin tubulin. tubulin.tubulin.

VinorelbineVinorelbineVinorelbine is isis a aa semi-synthetic semi-syntheticsemi-synthetic indoleindoindolele basedbased alkaloidalkaloid extracted extracted from from C.C. roseusroseus (Figure(Figure 77).7).). ItIt isis aa aknownknown known microtubulemicrotubule microtubule inhibitorinhibitor inhibitor withwith with selectivityselectivity selectivity towardtoward towardsss mitoticmitotic mitotic microtubules.microtubules. microtubules. ItIt disruptsdisrupts It disrupts thethe mitoticmitotic the mitoticspindlespindle spindle formationformation formation andand ultimatelyultimately and ultimately preventsprevents prevents cellcell cell division.division. division. VinorelbineVinorelbine Vinorelbine isis is usedused used inin combinationcombinationcombination chemotherapychemotherapychemotherapy with withwith cisplatin cisplatincisplatin and andand cetuximab cetuximabcetuximab to toto treat treatreattNSCLC NSCLCNSCLC[ [77].77[77].]. Besides BesidesBesides vinorelbine, vinorelbine,vinorelbine, vinflunine vinfluninevinflunine was waswas alsoalsoalso shown shownshown to toto have havehave the thethe potential potentialpotential to treattoto treattreat the the NSCLCthe NSCLCNSCLC in the inin adjuvant thethe adjuvantadjuvant chemotherapy chemotherapychemotherapy with platinum-based withwith platinum-platinum- drugsbasedbased (Figure drugsdrugs 4 (Figure(Figure)[ 78]. Among 44)) [78].[78]. the AmongAmong other the counterparts,the otherother counterparts,counterparts, such as vincristine, suchsuch asas vinblastine,vincristine,vincristine, andvinblastine,vinblastine, vinorelbine, andand vinfluninevinorelbine,vinorelbine, is vinfluninefoundvinflunine to have isis foundfound higher toto activitieshavehave higherhigherin vivo actiactivitiesvitieswith in lowin vivovivo drug withwith resistance. lowlow drugdrug Therefore, resistance.resistance. vinflunine Therefore,Therefore, hasvinfluninevinflunine evolved hashas to be evolvedevolved a more toto potent bebe aa moremore drug potepote in lungntnt drugdrug cancer inin lung treatmentlung cacancerncer [33 treatmenttreatment]. [33].[33]. CongCongCong et etet al. al.al. reported reportedreported an anan indole-chalcone indole-chalconeindole-chalcone derivativederivativederivative ((FC77(FC77FC77,,, Scheme SchemeScheme6 6))6) that thatthat can cancan arrest arrestarrest cancer cancercancer cell cellcell growthgrowthgrowth by byby binding bindingbinding to toto tubulin, tubulin,tubulin, exhibiting exhibitingexhibiting a aa similar similarsimilar mechanism mechanismmechanismof ofofaction actionactionas asascolchicine. colchicine.colchicine.FC77 FC77FC77exhibited exhibitedexhibited aaa potent potentpotent growthgrowth inhibitor inhibitor ofof aa a majoritymajority majority ofof of NCI-60NCI-60 NCI-60 humanhuman human cancercancer cancer cellcell cell lineslines lines withwith with GI50GI50 GI50 ~~ 66 ~μμMM 6 µ [79].[79].M[ 79TheThe]. Theabilityability ability ofof FC77FC77 of FC77 toto retaintoretain retain itsits its cytotoxicitycytotoxicity cytotoxicity againstagainst against multi-drugmulti-drug multi-drug resistantresistant resistant cancercancer cancer cellcell lines lineslines (with(with nanomolar nanomolarnanomolar GIGIGI values) values)values) and andand low lowlow cytotoxicity cytotoxicitycytotoxicity levels levelslevels towards towardstowards normal normnormalal mobilized mobilizedmobilized peripheral peripheralperipheral blood bloodblood cells cellscells revealed revealedrevealed that thatthat FC77FC77FC77may maymay be bebe a aa potential potentialpotential therapeutic therapeutictherapeutic agent agentagent in inin treating treatingtreating multi-drug multi-drugmulti-drug resistant resistantresistant cancerscancerscancers suchsuchsuch asasas NSCLC.NSCLC.NSCLC. Moreover,Moreover,Moreover, the thethe direct directdirect interaction interactioninteraction of ofofFC77 FC77FC77with withwithtubulin tubulintubulinand andandinhibition inhibitioninhibition of ofofmicrotubule microtubulemicrotubule dynamics dynamicsdynamics with withwith ICICIC505050 valuesvalues ofofof 333 nMnMnM compared comparedcompared to toto popular popularpopular drugs drugsdrugs such suchsuch as asas paclitaxel paclitaxelpaclitaxeland andand vincristine vincristinevincristine with withwith IC ICIC505050 values valuesvalues of ofof 141414 nM nMnM and andand 37 3737 nM, nM,nM, respectively, respectively,respectively, makes makesmakes it it anit anan attractive attractiveattractive microtubule-targeting microtubule-targetingmicrotubule-targeting agent agentagent for forfor the thethe treatment treatmenttreatment of multidrug-resistantofof multidrug-resistantmultidrug-resistant cancers cancerscancers [79 ]. [79].[79].

OO OO OO HH COCO H CO 33 PiperidinePiperidine H33CO

EtOH,EtOH, 95 95 ° ° C C NHNH HH33COCO NN HH33COCO HH OCHOCH33 8.2%8.2% yield yield OCHOCH33 4040 4141 FC77FC77 SchemeSchemeScheme 6. 6.6. Synthesis SynthesisSynthesis of ofof FC77 FC77FC77 adapted adaptedadapted from fromfrom the thethe reference referencereference [ [79].79[79].].

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TheThe synthesis of of FC77FC77 waswas accomplished accomplished in in a asingle single step, step, as asshown shown in Scheme in Scheme 6 [79].6[ The79]. Thecondensation condensation reaction reaction between between the the acetophenone acetophenone derivative derivative (40) (40 )with with the the indole-3-carboxaldehyde ((4141)) inin thethe presencepresenceof ofpiperidine piperidine a affordedfforded the the target target compound compound ( FC77(FC77).). DasDas etet al.al. recentlyrecently synthesizedsynthesized aa seriesseries ofof sixsix bis(indolyl)-hydrazide bis(indolyl)-hydrazide−hydrazoneshydrazones (NMK-BH(NMK-BH − compounds),compounds), inin orderorder toto developdevelop novelnovel andand eefficienfficientt microtubule-targetingmicrotubule-targeting chemotherapeuticchemotherapeutic agentsagents againstagainst lunglung cancer.cancer. TheyThey achievedachieved thisthis byby linkinglinking thethe twotwo indoleindole ringsrings withwith an active pharmacophore linker,linker, asas shownshown inin SchemeScheme7 .7. CytotoxicityCytotoxicity studiesstudies ofof thesethese compounds compounds againstagainst human human lung lung adenocarcinomaadenocarcinoma A-549A-549 cellscells revealedrevealed thatthat NMK-BH3NMK-BH3 withwith thethe electron-donatingelectron-donating 5-OMe5-OMe groupgroup andand thethe indoleindole ringsrings tetheredtethered toto thethe C-2C-2 positionposition ofof thethe indole-Aindole-A waswas foundfound toto bebe moremore potentpotent thanthan otherother combinations.combinations. TheThe mechanismmechanism ofof actionaction ofof NMK-BH3NMK-BH3 inin NSCLCNSCLC (A549(A549 cells)cells) revealedrevealed thethe disruptiondisruption ofof thethe mitoticmitotic spindlespindle andand depolymerizationdepolymerization ofof thethe interphaseinterphase microtubulemicrotubule networknetwork ultimatelyultimately ledled toto apoptoticapoptotic cellcell death.death. ThisThis isis signifiedsignified byby thethe overexpressionoverexpression ofof Bax,Bax, p53,p53, caspasecaspase 3,3, andand caspasecaspase 99 andand decreasedecrease inin thethe Bcl-2Bcl-2 expressionexpression [[80].80]. TheirTheir experimentsexperiments revealedrevealed thatthat NMK-BH3NMK-BH3 waswas moremore sensitivesensitive toto humanhuman lunglung adenocarcinomaadenocarcinoma A549 A549 cells cells with with IC IC5050of of ~2~2 µμM, while highly resistant toto normal humanhuman lunglung fibroblastsfibroblasts (WI38)(WI38) withwith ICIC5050 of 48.5 µμM (24 fold).

a) dil. H2SO4, EtOH, reflux 80−90% yield NHNH N 2 N COOH b) NH NH ,H O H 2 2 2 H EtOH, reflux O AcOH, EtOH H 85−90% yield 43 reflux N OCH3 42 N N O H 80% yield O H3CO N DMF, POCl3 H3CO H H NMK-BH3 N H 90-95% yield N H 44 45 SchemeScheme 7.7. SynthesisSynthesis ofof NMK-BH3NMK-BH3 adaptedadapted fromfrom thethe referencereference [[80].80].

TheThe synthesissynthesis ofof NMK-BH3NMK-BH3 waswas achievedachieved asas shownshown inin SchemeScheme7 [7 [80].80]. AA solutionsolution ofof indole-2-indole-2- carboxyliccarboxylic acidacid ((4242)) waswas refluxedrefluxed inin ethanolethanol withwith aa catalyticcatalytic amountamount ofof dilutedilute sulfuricsulfuric acid,acid, toto obtainobtain thethe correspondingcorresponding ethylethyl esterester intermediate,intermediate, whichwhich waswas treatedtreated withwith hydrazinehydrazine hydratehydrate toto obtainobtain thethe intermediateintermediate43 43.. OnOn thethe otherother hand,hand, thethe preparationpreparation ofof thethe indole-3-carboxaldehydeindole-3-carboxaldehyde 4545,, viavia treatmenttreatment ofof thethe methoxymethoxy indoleindole 4444 withwith phosphorousphosphorous oxychlorideoxychloride andand anhydrousanhydrous DMF. Finally,Finally, condensationcondensation ofof hydrazidehydrazide intermediateintermediate 4343 andand indole-3-carboxaldehydeindole-3-carboxaldehyde 4545 inin thethe presencepresence ofof aa catalyticcatalytic amountamount ofof glacialglacial aceticacetic acid,acid, andand thethe mixturemixture waswas refluxedrefluxed atat 8080◦ °CC forfor 55 h.h. TheThe resultingresulting mixturemixture waswas thenthen cooledcooled toto collectcollect thethe desireddesired targettarget ((NMK-BH3NMK-BH3).).

2.9. Inhibition of DNA-Topoisomerases 2.9. Inhibition of DNA-Topoisomerases Owing to the and acute toxicity associated with lung cancer treatment, Owing to the drug resistance and acute toxicity associated with lung cancer treatment, the the combination of two or more pharmacophores has become an attractive strategy in drug discovery combination of two or more pharmacophores has become an attractive strategy in drug discovery and has evolved as an effective tool in treating lung cancer patients. To overcome the multi-drug and has evolved as an effective tool in treating lung cancer patients. To overcome the multi-drug resistance in NSCLC patients, Chen et al. adapted the above strategy and developed hybrid molecules to resistance in NSCLC patients, Chen et al. adapted the above strategy and developed hybrid molecules improve drug efficacy. They designed and synthesized a series of indolizino[6,7-b]indoles, incorporating to improve drug efficacy. They designed and synthesized a series of indolizino[6,7-b]indoles, two pharmacophores: β-carboline group and a bis(hydroxymethyl)pyrrole group with topoisomerase incorporating two pharmacophores: β-carboline group and a bis(hydroxymethyl)pyrrole group with (Topo) I/II inhibition and DNA cross-linking abilities respectively [81,82] (Figure8). The hybrid topoisomerase (Topo) I/II inhibition and DNA cross-linking abilities respectively [81,82] (Figure 8). derivative (BO-1978) was found to be effective in the suppression of lung adenocarcinoma A549 cells The hybrid derivative (BO-1978) was found to be effective in the suppression of lung adenocarcinoma through the inhibition of Topo I/II and the induction of DNA cross-links resulting in DNA damage A549 cells through the inhibition of Topo I/II and the induction of DNA cross-links resulting in DNA and a resulting cell cycle arrest. The hybrid derivative (BO-1978) was synthesized as shown in damage and a resulting cell cycle arrest. The hybrid derivative (BO-1978) was synthesized as shown Scheme8[81,82]. in Scheme 8 [81,82].

Molecules 2019, 24, x FOR PEER REVIEW 12 of 26

CO Me CO Me CO2Me CO2Me 2 2 NaH, MeI HCHO EtCOCl O O NH2 NH N THF N MeOH TEA N N N Et 67% yield N Et 63% yield 60% yield H H H Me 43 44 45 46

MeO2C HOH2C DMAD CO2Me CH2OH Ac2O LiAlH4,Ether N DCM, 0 °C N 60-75 °C Et Et N N 64% yield 67% yield Me Me 47 BO-1978 Scheme 8. Synthesis of BO-1978 adapted from the references [81] and [82].

The tetrahydro-β-carboline 44 was synthesized by adding to L-tryptophan methyl ester hydrochloride (43). The reaction of compound 44 with propionyl chloride in triethylamine provided the amide (45). The of the indole intermediate (45) was methylated using and methyl iodide to generate the compound 46. The reaction of 46 with dimethyl acetylenedicarboxylate (DMAD) in acetic anhydride yielded the diester 47, which was further reduced with lithium aluminum hydride to afford the desired compound (BO-1978) (Scheme 8). The hybrid derivative compound (BO-1978) showed the synergistic effect of both the pharmacophores, which incorporates the anti-proliferative activity and Topo I and Topo II inhibition of β-carboline and the potent anti-tumor activity of bis-hydroxy-methylpyrrole, which is known to induce the DNA cross-linking (Figure 8). MoleculesIn 2020the , same25, 1615 front, Chang et al. developed a series of novel indolizino[8,7-b]indole hybrids12 of 25 (Figure 9) [83].

Molecules 2019, 24Figure, x FOR PEER 8. Biological REVIEW significance of bis(hydroxymethyl)pyrrole and β-carboline. 12 of 26 Figure 8. Biological significance of bis(hydroxymethyl)pyrrole and β-carboline. CO Me CO Me CO2Me CO2Me 2 2 NaH, MeI HCHO EtCOCl O O As shownNH2 in Figure 8, the substituentNH on the indole nitrogenN is foundTHF to play a key roleN in MeOH TEA N N N Et 67% yield N Et determining the activity63% yield of the hybrid molecule.60% yieldThe presenceH of –Me group (53) makes them potent H H Me Molecules 2019, 24, x FOR PEER REVIEW 13 of 26 DNA43 cross-linking agents, whereas 44 –NH derivatives (52) are45 potent TOPO-II inhibitors. The 46 resulting compounds were most sensitive to SCLC (H526) cells both in vitro and in vivo studies. One of the O CH MeO2C HOH C 3 Me compounds 52glyoxylic, was acid found to have potent Topo II inhibitory2 activity withN significant tumor DMAD NH2 NH H C Cl N KOH, H O CO2Me 3 O CHAc2OH2O suppressionAc O in nude2 mice bearing LiAlHSCLC4,Ether H526 xenografts (Scheme 9). Compound 52 wasOCH3 shown to 2 O O N NaOH N DMAD N N N N H be moreH potent75% than yield cisplatinHEt and etoposideDCM, 0 °C and possessedH HO the comparable potency ofO irinotecan [83]. 60-75 °C HO Acetone Et72% yield O N N OCH3 64%48 yield 4967%71% yield yield 50 51 Me Me LiAlH4, ether NaH, MeI 47 BO-1978 DCM, 0 °C DMF

SchemeScheme 8. Synthesis 8. Synthesis of BO-1978 of BO-1978 adapted adapted from from the the references referencesMe [81] [81 and,82 ].[82]. Me N N OH OH The tetrahydro-β-carboline 44 was synthesized by adding formaldehydeN to L-tryptophanN methyl The tetrahydro-β-carboline 44 was synthesized by adding formaldehydeH to L-tryptophan methyl Me esterester hydrochloridehydrochloride ((4343).). The reaction of compoundcompound 44 withwith propionylpropionylOH chloridechloride inin triethylaminetriethylamineOH 52 90% yield 53 65% yield providedprovided the amide amide (45 (45).). The The nitrogen nitrogen of the of indole the indole intermediate intermediate (45) was (45 methylated) was methylated using sodium using sodiumhydride hydrideand methylScheme and methyl iodide9. Synthesis iodide to generateof tocompounds generate the 52 thecompound and compound 53, adapted 46. 46The from. The reaction the reaction reference of of 46[83].46 with dimethyldimethyl acetylenedicarboxylate acetylenedicarboxylate (DMAD) (DMAD) in in acetic acetic anhydride anhydride yielded yielded the diester the diester47, which 47, waswhich further wasreduced further withreduced lithiumThe with synthesis aluminum lithium of aluminum compounds hydride to hydrid a ff52ord ande theto afford53 desired is shown the compound desired in Scheme compound (BO-1978 9 [83]. )(BO-1978) (Scheme Briefly,8 ).(Schemethe reaction 8). of tryptamineTheThe hybridhybrid hydrochloride derivativederivative (48 compound)compound with an aqueous (BO-1978 solution)) showedshowed of glyoxalic thethe synergisticsynergistic acid and potassium eeffectffect ofof hydroxide bothboth thethe pharmacophores,pharmacophores,generated the tetrahydro- whichwhich incorporatesincorporatesβ-carboline thetheintermediate anti-proliferativeanti-proliferative (49). Compound activityactivity andand 50 was Topo prepared II andand TopoTopo by IItheII inhibitioninhibition addition ofofof β βacetyl-carboline-carboline chloride andand to thethe 49, potentpotent then DMAD anti-tumoranti-tumor was activity activityadded to ofof compound bis-hydroxy-methylpyrrole,bis-hydroxy-methylpyrrole, 50 in acetic anhydride whichwhich generated isis knownknown the toto induceinducetetracyclic thethe DNADNAdiesters cross-linkingcross-linking (51). Finally, (Figure(Figure the 8reduction ).8). of 51 with lithium aluminum hydride afforded the desiredInIn the thetetracyclic samesame front,front, diol ( Chang52Chang), while etet al.theal. treatment developeddeveloped of aa intermediate seriesseries ofof novelnovel 51 with indolizino[8,7-b]indoleindolizino[8,7-b]indole sodium hydride and hybridshybrids methyl (Figure(Figureiodide 9resulted 9))[ 83[83].]. in desired N-methyl-tetracyclic diol (53).

FigureFigure 9.9. DesignDesign ofof indolizino[6,7-b]indoleindolizino[6,7-b]indole andand indolizino[8,7-b]indoleindolizino[8,7-b]indole derivatives.derivatives.

AsIn an shown attempt in Figure to develop8, the effective substituent Topo-II on the inhibitors indole nitrogenas potent is anti-cancer found to play agents, a key Song role et in al. determiningsynthesized thea Figurenovel activity 8.series Biological of theof hybridbisindolylalkanes significance molecule. of bis(hydroxymethyl)pyrrole Theanalogs presence such of as –Me 3,3′-(thiochroman-4,4-diyl)bis(1H- group and β-carboline. (53) makes them potent DNAindole) cross-linking and tested agents,against whereas a variety –NH of human derivatives cancer (52 )cell are lines potent (Scheme TOPO-II 10 inhibitors.). Notable Theamong resulting them, As shown in Figure 8, the substituent on the indole nitrogen is found to play a key role in compoundscompounds were57(a-c) most were sensitive found to to be SCLC potent (H526) against cells A549 both cellsin vitrowith andIC50 valuesin vivo ofstudies. ~9 μg/mL One [84]. of the compoundsdetermining52 the, was activity found of to the have hybrid potent molecule. Topo II inhibitory The presence activity of –Me with group significant (53) makes tumor suppressionthem potent DNA cross-linking agents, whereas –NH derivatives (52) are potent TOPO-II inhibitors. The resulting compounds were most sensitive to SCLC (H526) cells both in vitro and in vivo studies. One of the compounds 52, was found to have potent Topo II inhibitory activity with significant tumor suppression in nude mice bearing SCLC H526 xenografts (Scheme 9). Compound 52 was shown to be more potent than cisplatin and etoposide and possessed the comparable potency of irinotecan [83].

Scheme 10. Synthesis of compounds 57(a–c) adapted from reference [84].

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O CH3 Me glyoxylic acid N NH2 NH H C Cl N KOH, H O 3 O Ac2O 2 OCH3 O O N N NaOH N DMAD N H 75% yield H H O H HO Acetone HO O 72% yield OCH3 48 4971% yield 50 51 LiAlH4, ether NaH, MeI DCM, 0 °C DMF Molecules 2020, 25, 1615 13 of 25 Me Me N N OH OH in nude mice bearing SCLC H526 xenografts (Scheme9). CompoundN 52 was shown to beN more potent H Me thanMolecules cisplatin 2019, 24 and, x FOR etoposide PEER REVIEW and possessed the comparable potency ofOH irinotecan [83]. OH13 of 26 52 90% yield 53 65% yield O Scheme 9. Synthesis of compounds 52 and 53, adaptedCH3 from the reference [83].Me glyoxylic acid N NH2 NH H C Cl N KOH, H O 3 O Ac2O 2 OCH3 O O N N NaOH N DMAD N TheH synthesis75% yield of compounds 52 and 53 is shownH in Scheme 9 [83]. HBriefly, Othe reaction of H HO Acetone HO O 72% yield OCH3 tryptamine48 hydrochloride (48 49) with an71% aqueous yield solution 50 of glyoxalic acid and 51 potassium hydroxide generated the tetrahydro-β-carboline intermediate (49). CompoundLiAlH4, ether50 was prepared NaH,by the MeI addition DCM, 0 °C DMF of acetyl chloride to 49, then DMAD was added to compound 50 in acetic anhydride generated the Me Me tetracyclic diesters (51). Finally, the reduction of 51 with lithium Naluminum hydride affordedN the desired tetracyclic diol (52), while the treatment of intermediate 51 with sodiumOH hydride and methylOH N N H iodide resulted in desired N-methyl-tetracyclic diol (53). Me OH OH 52 90% yield 53 65% yield Scheme 9. Synthesis of compounds 52 and 53, adapted from the reference [[83].83].

The synthesis of compounds 52 andand 5353 isis shownshown inin SchemeScheme9 [9 [83].83]. Briefly, Briefly, the reaction of tryptamine hydrochloride (48) with an aqueous solution of glyoxalic acid and potassium hydroxide generated the tetrahydro-ββ-carboline intermediate (49). Compound 50 was prepared by the addition of acetyl chloride to 4949,, thenthen DMADDMAD waswas addedadded toto compoundcompound 50 inin aceticacetic anhydrideanhydride generatedgenerated thethe tetracyclic diesters (51). Finally, Finally, the the reduction reduction of of 51 with lithium aluminum hydride afforded afforded the desired tetracyclicFigure diol9. Design (52), of while indolizino[6,7-b]indole the treatment of intermediateand indolizino[8,7-b]indole 51 with sodium derivatives. hydride and methyl iodide resultedresulted inin desireddesired N-methyl-tetracyclicN-methyl-tetracyclic dioldiol ((5353).). InIn an an attempt attempt to to develop develop effective effective Topo-II Topo-II inhibitors as as potent potent anti-cancer anti-cancer agents, agents, Song Song et et al. al. synthesizedsynthesized a anovel novel series series of bisindolylalkanes of bisindolylalkanes analogs analogs such as such 3,3′-(thiochroman-4,4-diyl)bis(1H- as 3,30-(thiochroman-4,4-diyl) indole)bis(1H-indole) and tested and against tested againsta variety a varietyof human ofhuman cancer cancercell lines cell (Scheme lines (Scheme 10). Notable 10). Notable among among them, compoundsthem, compounds 57(a-c)57(a-c were) found were found to be potent to be potent against against A549 A549 cells cellswith withIC50 values IC50 values of ~9 ofμg/mL ~9 µg [84]./mL [84].

Figure 9. Design of indolizino[6,7-b]indole and indolizino[8,7-b]indole derivatives.

In an attempt to develop effective Topo-II inhibitors as potent anti-cancer agents, Song et al. synthesized a novel series of bisindolylalkanes analogs such as 3,3′-(thiochroman-4,4-diyl)bis(1H- indole) and tested against a variety of human cancer cell lines (Scheme 10). Notable among them, compounds 57(a-c) were found to be potent against A549 cells with IC50 values of ~9 μg/mL [84].

SchemeScheme 10. 10. SynthesisSynthesis of of compounds compounds 5757((a–ca–c)) adapted adapted from from reference reference [84]. [84].

The synthetic scheme of compounds 57(a–c) was shown in Scheme 10[ 84]. The first step involved the condensation of substituted benzene thiols 54(a–c) with 3-chloropropanoic acid and sodium hydroxide in water, followed by treatment of corresponding intermediate 55(a–c) with concentrated sulfuric acid to obtain the intermediates 56(a–c). A mixture of indole (7) and substituted

Scheme 10. Synthesis of compounds 57(a–c) adapted from reference [84].

Molecules 2019, 24, x FOR PEER REVIEW 14 of 26 Molecules 2019, 24, x FOR PEER REVIEW 14 of 26

The synthetic scheme of compounds 57(a–c) was shown in Scheme 10 [84]. The first step The synthetic scheme of compounds 57(a–c) was shown in Scheme 10 [84]. The first step involved the condensation of substituted benzene thiols 54(a–c) with 3-chloropropanoic acid and involved the condensation of substituted benzene thiols 54(a–c) with 3-chloropropanoic acid and Moleculessodium2020 hydroxide, 25, 1615 in water, followed by treatment of corresponding intermediate 55(a–c)14 with of 25 sodium hydroxide in water, followed by treatment of corresponding intermediate 55(a–c) with concentrated sulfuric acid to obtain the intermediates 56(a–c). A mixture of indole (7) and substituted concentrated sulfuric acid to obtain the intermediates 56(a–c). A mixture of indole (7) and substituted thiochroman-4-ones 56(a–c), in the presence of silicotungstic acid was refluxed in ethanol yielded the thiochroman-4-ones 5656(a–c(a–c),), in the presence of silicotungstic acid was refluxedrefluxed in ethanol yielded the desired compounds (57(a–c)). desired compounds (5757(a–c(a–c)).)). Makaluvamine is an indole based alkaloid metabolite isolated from a marine sponge Zyzzya. Makaluvamine is an indole based alkaloid metabolite isolated from from a marine sponge Zyzzya. This compound showed significant cytotoxic activity and DNA topoisomerase II inhibition [85]. This compound showed significant significant cytotoxic activity and DNA topoisomerase II II inhibition inhibition [85]. [85]. Nadkarni et al. synthesized a series of makaluvamine analogs and studied their biological activities Nadkarni et al. synthesized a series of makaluvamine analogs and studied their biological activities against various human lung cancer cell lines (Scheme 11). One of the compounds (60) was found to against various human human lung lung cancer cancer cell cell lin lineses (Scheme (Scheme 11). 11). One One of ofthe the compounds compounds (60 ()60 was) was found found to be most potent against human lung cancer cell lines of both human adenocarcinoma (A549) and tobe bemost most potent potent against against human human lung lung cancer cancer cell cell lines lines of of both both human human adenocarcinoma (A549) and carcinoma (H1299) cells with IC50 of 0.3 and 0.58 μM, respectively. Further studies revealed that the carcinoma (H1299) cells with IC50 ofof 0.3 0.3 and 0.58 μµM, respectively. Further studies revealed that the compound induced both apoptosis and S-phase cell cycle arrest [86]. compound induced both apoptosis andand S-phase cellcell cyclecycle arrestarrest [[86].86].

Scheme 11. Synthesis of compound 60 adapted from reference [86]. Scheme 11. Synthesis of compound 60 adapted from reference [[86].86].

The synthesis of makaluvamine 60 is represented in Scheme 11 [86]. Compound 60 was The synthesis of makaluvaminemakaluvamine 6060 isis representedrepresented inin SchemeScheme 1111[ 86[86].]. Compound 60 was synthesized in one-step synthesis from the tricyclic compound 58. Condensation of compound 58 synthesized in in one-step one-step synthesis synthesis from from the the tricyclic tricyclic compound compound 5858. Condensation. Condensation of ofcompound compound 58 with 4-chloro-benzylamine (59) in anhydrous methanol followed by treatment with trifluoroacetic 58withwith 4-chloro-benzylamine 4-chloro-benzylamine (59 (59) in) inanhydrous anhydrous methanol methanol followed followed by by treatment treatment with with trifluoroacetic trifluoroacetic acid (TFA) afforded the desired makaluvamine compound (60). acid (TFA) aaffordedfforded thethe desireddesired makaluvaminemakaluvamine compoundcompound ((6060))..

2.10.2.10. Histone Deacetylase (HDAC) Inhibitors 2.10. Histone Deacetylase (HDAC) Inhibitors HDACHDAC enzymesenzymes are involvedinvolved inin aa varietyvariety ofof cellularcellular processesprocesses suchsuch asas cellcell proliferation,proliferation, cellcell HDAC enzymes are involved in a variety of cellular processes such as cell proliferation, cell didifferentiation,fferentiation, andand apoptosisapoptosis [[87].87]. Research studies show that thethe dysregulationdysregulation ofof HDACHDAC cancan leadlead differentiation, and apoptosis [87]. Research studies show that the dysregulation of HDAC can lead toto several types types of of tumor tumor malignancies. malignancies. HDAC HDAC inhibi inhibitorstors have, have, thus, thus, evolved evolved as a asnew a newclass classof anti- of to several types of tumor malignancies. HDAC inhibitors have, thus, evolved as a new class of anti- anti-cancercancer agents agents because because of their of their efficacy efficacy to arrest to arrest cell cellgrowth, growth, cell celldifferentiation, differentiation, and and cell cell death death by cancer agents because of their efficacy to arrest cell growth, cell differentiation, and cell death by byapoptosis apoptosis [88,89]. [88,89 In]. this In thisdirection, direction, Han Han et al. et investigated al. investigated the anti-cancer the anti-cancer activity activity of A549 of A549and H441 and apoptosis [88,89]. In this direction, Han et al. investigated the anti-cancer activity of A549 and H441 H441lung lungcancer cancer cells cellsusing using twotwo novel novel cyclic cyclic amide- amide-bearingbearing hydroxamic hydroxamic acid-based acid-based HDAC HDAC inhibitors lung cancer cells using two novel cyclic amide-bearing hydroxamic acid-based HDAC inhibitors SL142SL142 andand SL325SL325.. Their studies revealed that both derivativesderivatives showed more potentpotent cellcell growthgrowth SL142 and SL325. Their studies revealed that both derivatives showed more potent cell growth inhibitioninhibition andand cell cell death death than than the hydroxamic the hydroxamic acid-based acid-based HDAC inhibitor HDAC suberoylanilide inhibitor suberoylanilide hydroxamic inhibition and cell death than the hydroxamic acid-based HDAC inhibitor suberoylanilide acidhydroxamic (SAHA) acid (Figure (SAHA) 10). Besides,(Figure 10). these Besides, compounds these cancompounds also induce can significantalso induce caspase significant activity caspase and hydroxamic acid (SAHA) (Figure 10). Besides, these compounds can also induce significant caspase subGactivity0/G and1 population subG0/G1 in population human epithelial in human (H441) epithelial and adenocarcinoma (H441) and adenocarcinoma (A549) lung cancer (A549) cells, lung thereby cancer activity and subG0/G1 population in human epithelial (H441) and adenocarcinoma (A549) lung cancer demonstratingcells, thereby demonstrating that they are more that they effective are more than SAHAeffective[90 than,91]. SAHA [90,91]. cells, thereby demonstrating that they are more effective than SAHA [90,91].

O O O O O O O OH O OH N O N OH OH N N NH O H O NH N H H O N H HOHN N OH HOHN N N OH N N O H ONS O H 2 O2S

N N N N SAHA SL142 SL325 61 SAHA SL142 SL325 61 Figure 10. Structure of compounds suberoylanilide hydroxamic acidacid (SAHA),(SAHA), SL142,SL142, SL325,SL325, andand 6161.. Figure 10. Structure of compounds suberoylanilide hydroxamic acid (SAHA), SL142, SL325, and 61. A new class of 1-arylsulfonyl-5-N-hydroxyacrylamide indoles was reported by Lai et al., as potent histone deacetylase inhibitors. Further investigation revealed that the lead compound 61 demonstrated µ GI50 of 1 M against the A549 cell lines. They demonstrated that the N-hydroxyacrylamide group located at the C-5 position of indole ring was more potent than other derivatives. When the group Molecules 2019, 24, x FOR PEER REVIEW 15 of 26

A new class of 1-arylsulfonyl-5-N-hydroxyacrylamide indoles was reported by Lai et al., as potent histone deacetylase inhibitors. Further investigation revealed that the lead compound 61 demonstrated GI50 of 1 μM against the A549 cell lines. They demonstrated that the N- Molecules 2020, 25, 1615 15 of 25 hydroxyacrylamide group located at the C-5 position of indole ring was more potent than other derivatives. When the group tested the efficacy of the compounds on a human xenograft model in testednude mice the e ffibearingcacy of A549 the compounds lung cancer on cell a humanlines, compound xenograft 61 model was infound nude to mice be more bearing effective A549 lungthan cancerSAHA cell(Figure lines, 10). compound The authors61 was found found that tothere be morewas a e ff47%ective tumor than growth SAHA delay (Figure (32% 10). tumor The authors growth foundinhibition) thatthere by or wasal administration a 47% tumor growth with compound delay (32% 61 tumor daily growth at 200 inhibition)mg/ kg showing by oral its administration efficacy as a withpotential compound anti-lung61 dailycancer at agent 200 mg [92]./ kg showing its efficacy as a potential anti-lung cancer agent [92]. DacinostatDacinostat (NVPLAQ824)(NVPLAQ824) is is an an HDAC HDAC inhibitor inhibitor introduced introduced by by Novartis Novartis in 2003in 2003 and and is used is used as anas anti-canceran anti-cancer agent agent (Scheme (Scheme 12)[ 1293)]. [93]. Dacinostat Dacinostat was foundwas found to inhibit to inhibit an HDAC an HDAC enzyme enzyme isolated isolated from H129from H129 cell lysates cell lysates with awith potency a potency of 32 of nM 32 andnM humanand human lung lung cancer cancer cells cell (H1299)s (H1299) with with a potency a potency of 150of 150 nM, nM, respectively. respectively. Besides, Besides, it wasit was also also found found to to be be potent potent in in the thein in vivo vivostudies, studies, inin subjectsubject mice,mice, againstagainst humanhuman lunglung carcinomacarcinoma (A549(A549 andand HCT116)HCT116) sub-cutaneoussub-cutaneous xenografts.xenografts. DetailedDetailed studiesstudies ofof thethe mechanismmechanism ofof actionaction showed showed that that dacinostat dacinostat acts acts on on the the A549 A549 and and HCT116 HCT116 cells cells by by G2-M G2-M arrest arrest with with a significanta significant sub-G1 sub-G1 population, population, showing showing that that the the cells cells were were subjected subjected to apoptosisto apoptosis [94 [94–97].–97].

SchemeScheme 12.12. SynthesisSynthesis ofof dacinostatdacinostat adaptedadapted fromfrom thethe referencereference [[98].98].

TheThe synthesis of of dacinostat dacinostat is isshown shown in the in Scheme the Scheme 12 [98]. 12 [Briefly,98]. esterification Briefly, esterification of 4-formyl- of 4-formyl-cinnamiccinnamic acid followed acid followed by reductive by reductive amination amination with tryptamine with tryptamine 48, generated48, generated the condensed the condensed indole indole64. The64 resulting. The resulting intermediate intermediate 64 was64 alkylatedwas alkylated with with2-(tert-buty 2-(tert-butyldimethylsilyloxy-ethylbromideldimethylsilyloxy-ethylbromide (65) (afforded65) afforded the thetertiary tertiary amine 66.66 The. The methyl methyl ester ester of of 6666 waswas transformed transformed to to hydroxamic hydroxamic acid 6767,, followedfollowed byby deprotectiondeprotection yieldedyielded thethe desireddesired dacinostatdacinostat (Scheme(Scheme 12 12).).

2.11. Miscellaneous Indole Derivatives in Anti-Lung Cancer Treatment 2.11. Miscellaneous Indole Derivatives in Anti-Lung Cancer Treatment Lv et al. designed and synthesized a series of novel 1-(3-dimethyl-aminopropyl)indolin-2-one Lv et al. designed and synthesized a series of novel 1-(3-dimethyl-aminopropyl)indolin-2-one derivatives. Here the most active derivative was found to be more potent than sunitinib against derivatives. Here the most active derivative was found to be more potent than sunitinib against NSCLC (A549) cells. These compounds were tested for their antiproliferative activity against lung NSCLC (A549) cells. These compounds were tested for their antiproliferative activity against lung adenocarcinoma (A549) cells and they found that all the compounds showed potent activity. Among all adenocarcinoma (A549) cells and they found that all the compounds showed potent activity. Among generated compounds, compound 77 (Scheme 13) proved to be most potent with IC50 of 1.10–1.47 µM, all generated compounds, compound 77 (Scheme 13) proved to be most potent with IC50 of 1.10–1.47 which is 1.8–6 fold higher than sunitinib [99]. μM, which is 1.8–6 fold higher than sunitinib [99]. A representation of the synthesis of the most potent compound 77 is shown in Scheme 13[ 99,100]. Briefly, the reaction of tert-butyl acetoacetate 68 with sodium nitrite in acetic acid generated the oxime 69. The resulting oxime (69) was reacted with ethyl acetoacetate and powder in acetic acid yielded the pyrrole diesters (70). Ester hydrolysis of 70, followed by monodecarboxylation reaction in the presence of conc. HCl and ethanol yielded the ethyl ester 71. Then subsequent treatment of 71 with phosphorus oxychloride yielded the 72. The resulting intermediate (72) was hydrolyzed, followed by amide bond formation in the presence of morpholine and coupling reagents (EDC/HOBt) yielded compound 74. On the other hand, compound 76 was obtained through the treatment of intermediate 75 with 3-chloro-N,N-dimethyl-propan-1-amine in the presence of KF-alumina. Finally, Knoevenagel condensation of the intermediates 76 and 74, followed by HCl treatment generated the HCl salt of the desired target (77) (Scheme 13).

Molecules 2019, 24, x FOR PEER REVIEW 16 of 26

Molecules 2020, 25, 1615 16 of 25 Molecules 2019, 24, x FOR PEER REVIEW 16 of 26

Scheme 13. Synthesis of compound 77 adapted from references [99] and [100].

A representation of the synthesis of the most potent compound 77 is shown in Scheme 13 [99,100]. Briefly, the reaction of tert-butyl acetoacetate 68 with sodium nitrite in acetic acid generated the oxime 69. The resulting oxime (69) was reacted with ethyl acetoacetate and zinc powder in acetic acid yielded the pyrrole diesters (70). Ester hydrolysis of 70, followed by monodecarboxylation reaction in the presence of conc. HCl and ethanol yielded the ethyl ester 71. Then subsequent treatment of 71 with phosphorus oxychloride yielded the aldehyde 72. The resulting intermediate (72) was hydrolyzed, followed by amide bond formation in the presence of morpholine and coupling reagents (EDC/HOBt) yielded compound 74. On the other hand, compound 76 was obtained through the treatment of intermediate 75 with 3-chloro-N,N-dimethyl-propan-1-amine in the presence of KF- alumina. Finally,SchemeScheme Knoevenagel 13. 13.SynthesisSynthesis co ofndensation compound of compound 77of 77adaptedtheadapted intermediates from from references references 76 [99]and [99 and ,10074, [100].]. followed by HCl treatment generated the HCl salt of the desired target (77) (Scheme 13). DragmacidinDragmacidinA representation is is a a ofcytotoxic cytotoxic the synthesis bisalkaloid, bisalkaloid, of the isolated most isolated potent from from acompound marine a marine sponge 77 sponge is Dragmacidinshown Dragmacidin in Scheme sp. This sp.13 µ Thiscompound[99,100]. compound Briefly, proved provedthe to reaction be toa potent be of a potenttert-butyl antitumor antitumor acetoacetate agent. agent. It showed 68 It with showed IC sodium50 value IC50 nitriteofvalue 1–10 in ofμ aceticg/mL 1–10 againstacidg/mL generated againsthuman humanlungthe oxime cell lung lines 69. cell The (A549) lines resulting in (A549) the oximein in vitro the (in69 studies) vitro was studiesreacted(Figure (Figure with11) [101]. ethyl 11 )[ acetoacetate101]. and zinc powder in acetic acid yielded the pyrrole diesters (70). Ester hydrolysis of 70, followed by monodecarboxylation reaction in the presence of conc. HCl and ethanol yielded the ethyl ester 71. Then subsequent treatment of 71 with phosphorus oxychloride yielded the aldehyde 72. The resulting intermediate (72) was hydrolyzed, followed by amide bond formation in the presence of morpholine and coupling reagents (EDC/HOBt) yielded compound 74. On the other hand, compound 76 was obtained through the treatment of intermediate 75 with 3-chloro-N,N-dimethyl-propan-1-amine in the presence of KF- alumina. Finally, Knoevenagel condensation of the intermediates 76 and 74, followed by HCl treatment generated the HCl salt of the desired target (77) (Scheme 13). Dragmacidin is a cytotoxic bisalkaloid, isolated from a marine sponge Dragmacidin sp. This compound proved to be a potent antitumor agent. It showed IC50 value of 1–10 μg/mL against human FigureFigure 11.11. Structures ofof dragmacidin,dragmacidin, compoundscompounds 7878,, andand 7979((aa––cc).). lung cell lines (A549) in the in vitro studies (Figure 11) [101]. Recently,Recently, Zhao Zhao et et al. al. reported reported a series a series of indolyl of indo chalconeslyl chalcones that can that inhibit can inhibit lung cancer lung cellcancer growth. cell Ofgrowth. all the Of derivatives all the derivatives tested, they tested, found they compound found compound78 (Figure 1178) (Figure to be eff ective11) to inbe the effective induction in the of tumorinduction apoptosis. of tumor It inhibitedapoptosis. the It growthinhibited of the A549 growth cells byof A549 increasing cells by the increasing reactive oxygen the reactive species oxygen (ROS) levelsspecies and (ROS) by activation levels and of by the activation The nuclear of the factor The erythroidnuclear factor 2–related erythroid factor 2–related 2 (Nrf-2) factor pathway 2 (Nrf-2) [102]. Inpathway the in vivo [102].studies, In the in compound vivo studies,78 exhibited compound anti-growth 78 exhibited activity anti-growth of the tumor activity in of an the avian tumor embryo in an model,avian embryo showing model, the potential showing of the the potential compound of the as thecompound Nrf-2 activator as the Nrf-2 in cancer activator therapy. in cancer therapy. Hu et al. synthesized a series of indole derivatives with varying at 2 and 5 positions. The resulting compounds exhibited excellent anti-proliferative activity on lung cancer cell lines (H460 and A549) (Figure 11). Notably, compound 79a exhibited a high level of potency against A549 cells, with the IC value of 0.50 0.06 µM, while compounds 79b and 79c exhibited IC values of 0.16 50 Figure 11.± Structures of dragmacidin, compounds 78, and 79(a–c). 50 0.05 µM and 0.48 0.05 µM, respectively. Further detailed studies revealed that the compounds ± ± inducedRecently, apoptosis Zhao by et the al. inhibition reported ofa series of indolyl chalcones of Ser2 of thethat carboxyl-terminal can inhibit lung domaincancer cell of RNAgrowth. polymerase Of all the II, wherederivatives RNA polymerasetested, they IIfound is essential compound for messenger 78 (Figure RNA 11) (mRNA) to be effective synthesis in [103 the]. inductionHuang of et tumor al. further apoptosis. identified It inhibited a novel the indole growth derivative, of A549 SK228cells bythat increasing can effectively the reactive inhibit oxygen lung cancerspecies cell (ROS) lines levels by ROS and production by activation and of induce the The cell nuclear death factor by apoptosis. erythroid To 2–related evaluate factor the potency 2 (Nrf-2) of SK228pathwayagainst [102]. various In the in human vivo studies, cancer cell compound lines, the 78 authors exhibited treated anti-growth the cells with activity varying of the concentrations tumor in an avian embryo model, showing the potential of the compound as the Nrf-2 activator in cancer therapy.

Molecules 2019, 24, x FOR PEER REVIEW 17 of 26

Hu et al. synthesized a series of indole derivatives with varying substituents at 2 and 5 positions. The resulting compounds exhibited excellent anti-proliferative activity on lung cancer cell lines (H460 and A549) (Figure 11). Notably, compound 79a exhibited a high level of potency against A549 cells, withMolecules the 2019 IC50, 24 value, x FOR of PEER 0.50 REVIEW ± 0.06 μM, while compounds 79b and 79c exhibited IC50 values of 170.16 of 26± 0.05 μM and 0.48 ± 0.05 μM, respectively. Further detailed studies revealed that the compounds inducedHu etapoptosis al. synthesized by the ainhibition series of indoleof phosphorylation derivatives with of Ser2varying of the substituents carboxyl-terminal at 2 and 5domain positions. of RNAThe resulting polymerase compounds II, where exhibited RNA polymerase excellent anti-prolif II is essentialerative for activity messenger on lung RNA cancer (mRNA) cell lines synthesis (H460 [103].and A549) (Figure 11). Notably, compound 79a exhibited a high level of potency against A549 cells, withHuang the IC50 et value al. further of 0.50 identified ± 0.06 μ M,a novel while indole compounds derivative, 79b SK228and 79c that exhibited can effectively IC50 values inhibit of 0.16 lung ± cancer0.05 μ Mcell and lines 0.48 by ±ROS 0.05 production μM, respectively. and induce Further cell deathdetailed by stapoptosis.udies revealed To evaluate that the the compounds potency of SK228induced against apoptosis various by the human inhibition cancer of phosphorylation cell lines, the ofauthors Ser2 of treatedthe carboxyl-terminal the cells with domain varying of concentrationsRNA polymerase of SK228 II, where for 48RNA h. The polymerase resulting II IC is50 essentialvalues were for foundmessenger to be RNA3.4 and (mRNA) 0.3 μM synthesisfor A549 and[103]. H1299 cells respectively [104,105]. Further investigation of the mechanism of action showed that MoleculesSK228Huang 2020enhanced, 25et, 1615al. furthermitochondrial identified ROS a novel production indole derivative, and inflicted SK228 DNA that candamage effectively on cancer inhibit 17cells, lung of 25 ultimatelycancer cell leadinglines by to ROS intrinsic production mitochondria-dependent and induce cell death mitosis. by apoptosis. To evaluate the potency of SK228SK228 against was varioussynthesized human in cancera single cell step, lines, as thshowne authors in Scheme treated 14the [105]. cells Awith mixture varying of of SK228 for 48 h. The resulting IC values were found to be 3.4 and 0.3 µM for A549 and H1299 terephthalaldehydeconcentrations of SK228 (80) forand 48 5-hydroxy-indole h. The50 resulting IC(81)50 valuesin the werepresence found of to iodine be 3.4 afforded and 0.3 μ theM for desired A549 cellstetraindolesand H1299 respectively cells product respectively [104 (SK228,105].). Further[104,105]. investigation Further investigation of the mechanism of the mechanism of action of showed action showed that SK228 that enhancedSK228 enhanced mitochondrial mitochondrial ROS production ROS andproduction inflicted and DNA inflicted damage onDNA cancer damage cells, ultimately on cancer leading cells, toultimately intrinsic leading mitochondria-dependent to intrinsic mitochondria-dependent mitosis. mitosis. SK228SK228 waswas synthesizedsynthesized inin aa singlesingle step,step, asas shownshown inin SchemeScheme 1414[ 105[105].]. A mixturemixture ofof terephthalaldehydeterephthalaldehyde (8080)) andand 5-hydroxy-indole5-hydroxy-indole (8181)) in thethe presencepresence ofof iodineiodine aaffordedfforded thethe desireddesired tetraindolestetraindoles productproduct ((SK228SK228).).

Scheme 14. Synthesis of SK228 adapted from the reference [105].

Kim et al. synthesized a novel indirubin-3’-oxime derivative AGM130 with excellent anti-tumor activity and inhibition of cancer growth in A549 cells (Figure 12). Further investigation of the activity on A549 cells demonstrated that AGM130 induced caspase-dependent apoptosis via the mitochondria-mediatedSchemeScheme intrinsic 14.14. Synthesis pathway of [106]. SK228 adapted from thethe referencereference [[105].105]. Liu et al. reported a novel indolyl moiety 3-((7- ethyl-1H-indol-3-yl)-methyl)-2- methyl-quinolineKimKim etet al.al. synthesized (EMMQ) athat novel can indirubin-3indirubin-3’-oxime arrest cell-growth0-oxime derivativein NSCLC AGM130 (A549 and with H460) excellent cells (Figure anti-tumor 12). activityCellactivity growth and inhibition inhibition ofstudies of cancer cancer after growth growth 48 h in of A549 indose-dependent A549 cells cells (Figure (Figure treatment 12). Further12). indicated Further investigation investigation EMMQ of theIC50 activity values of the activityofon 8 A549μM on incells A549 both demonstrated cells the demonstratedA549 and that H460 thatAGM130 cellAGM130 lines. induced inducedThis processcaspase-dependent caspase-dependent involved the apoptosisdisruption apoptosis via viaof thethe mitochondria-mediatedmitochondrialmitochondria-mediated membrane intrinsicintrinsic potential, pathwaypathway DNA damage [[106].106]. and ultimately apoptotic cell death [107]. Liu et al. reported a novel indolyl quinoline moiety 3-((7- ethyl-1H-indol-3-yl)-methyl)-2- methyl-quinoline (EMMQ) that can arrest cell-growth in NSCLC (A549 and H460) cells (Figure 12). Cell growth inhibition studies after 48 h of dose-dependent treatment indicated EMMQ IC50 values of 8 μM in both the A549 and H460 cell lines. This process involved the disruption of the mitochondrial membrane potential, DNA damage and ultimately apoptotic cell death [107].

Figure 12. Structures of AGM130, EMMQ and tambjamine derivatives.

Liu et al. reported a novel indolyl quinoline moiety 3-((7- ethyl-1H-indol-3-yl)- methyl)-2-methyl-quinoline (EMMQ) that can arrest cell-growth in NSCLC (A549 and H460) cells (Figure 12). Cell growth inhibition studies after 48 h of dose-dependent treatment indicated EMMQ IC50 values of 8 µMFigure in both 12. theStructures A549 and of AGM130, H460 cell EMMQ lines. and This tambjamine process involved derivatives. the disruption of the mitochondrial membrane potential, DNA damage and ultimately apoptotic cell death [107]. To note, tambjamines are indole based marine alkaloids, known to be highly efficient transmembrane anion transporters in the model liposomes. They have widespread pharmacological applications (Figure 12). Studies have shown that these alkaloids can induce apoptosis in several cancer cell lines, rendering IC50 values in the micromolar range. Manresa et al. reported highly active indole based tambjamine derivatives, investigating their molecular mechanism of action. The results revealed that compounds 82 and 83 can induce apoptosis in lung cancer cells, in both in vitro and in vivo studies. Cytotoxicity is induced by the ROS activated stress kinase pathway. This occurs through the activation of P38 mitogen-activated protein kinase [108,109]. Evodiamine is an indole-containing alkaloid, isolated from a Chinese medicinal herb Evodia rutaecarpa (Wu-Chu-Yu). It has numerous pharmacological applications such as anti-inflammatory, Molecules 2019, 24, x FOR PEER REVIEW 18 of 26

To note, tambjamines are indole based marine alkaloids, known to be highly efficient transmembrane anion transporters in the model liposomes. They have widespread pharmacological applications (Figure 12). Studies have shown that these alkaloids can induce apoptosis in several cancer cell lines, rendering IC50 values in the micromolar range. Manresa et al. reported highly active indole based tambjamine derivatives, investigating their molecular mechanism of action. The results revealed that compounds 82 and 83 can induce apoptosis in lung cancer cells, in both in vitro and in Molecules 2019, 24, x FOR PEER REVIEW 18 of 26 vivo studies. Cytotoxicity is induced by the ROS activated stress kinase pathway. This occurs through the activationTo note, oftambjamines P38 mitogen-activated are indole proteinbased kinasemarine [108,109]. alkaloids, known to be highly efficient transmembraneEvodiamine anion is an transporters indole-containing in the model alkaloid, liposomes. isolated They from have a Chinese widespread medicinal pharmacological herb Evodia applicationsrutaecarpa (Wu-Chu-Yu). (Figure 12). StudiesIt has numerous have shown pharmacological that these alkaloids applications can induce such asapoptosis anti-inflammatory, in several anti-obesity, anti-viral, anti-tumor, and anti-nociceptive effects (Scheme 15). Studies have shown that cancer cell lines, rendering IC50 values in the micromolar range. Manresa et al. reported highly active indoleevodiamine based istambjamine capable of derivatives, strong anti-tumor investigating and cy totoxictheir molecular activity againstmechanism various of action. human The cancer results cell revealedlines (gastric, that compounds colon, liver, 82 lung, and and83 can breast). induce Detailed apoptosis mechanistic in lung cancer studies cells, by Zouin both et al. in revealedvitro and that in vivoevodiamine studies. Cytotoxicitycan exert the is anti-tumor induced by activity the ROS by ac thtivatede inhibition stress kinaseof Metadherin, pathway. which This occurs was identified through theas activationa novel oncogene of P38 mitogen-activated that is overexpressed protein in kinasemany [108,109].tumor malignancies [110]. Zou and his team Molecules 2020, 25, 1615 18 of 25 demonstratedEvodiamine that is thean treatmentindole-containing of NSCLC alkaloid, cells (A54 isolated9) with fromevodiamine a Chinese results medicinal in an increased herb Evodia level rutaecarpaof Bax expression. (Wu-Chu-Yu). This Itis hasfollowed numerous by a pharmacological decrease of Bcl-2 applications and MTDH, such which as anti-inflammatory, substantiated the anti-obesity,apoptotic mechanism anti-viral, of anti-tumor, action [111–113]. andand anti-nociceptiveanti-nocicep tive eeffectsffects (Scheme(Scheme 1515).). Studies have shown that evodiamine is capable of strong anti-tumor and cytotoxiccytotoxic activity against various human cancer cell O lines (gastric, colon, liver, lung,lung, andand breast).breast). Detailed mechanistic studies by Zou et al.al. revealed that NH2 N O evodiamine can exert the anti-tumor activity O by th thee inhibitionTFAA, DABCO of Metadherin, whichN was identifiedidentified as a novel oncogene that is overexpressed in many tumor malignancies [110]. ZouH and his team as a novel oncogene that is overexpressed in manyTriethoxymethane tumor malignancies [110]. Zou andN his team N N O H3C demonstratedH thatthat thethe treatmenttreatment of of NSCLC NSCLC cells cells (A549) (A549)DMA, with with 100evodiamine evodiamine °C, 5 h results results in in an an increased increased level level of CH ofBax Bax expression. expression. This This is followed is followed by a decreaseby 3a decrease of Bcl-2 of and Bcl-2 MTDH, and MTDH, which substantiated which substantiated the apoptotic the 71% yield apoptoticmechanism mechanism of action [ 111of action–113]. [111–113]. 48 84 Evodiamine Scheme 15. SynthesisO of evodiamine adapted from the reference [114]. NH2 N O O TFAA, DABCO N Evodiamine was synthesized as shown in Scheme 15 [114]. The reaction of tryptamineH (48) with Triethoxymethane N N-methylisatoicN anhydride (84) in theN presenceO of trifluoroacetic anhydride, 1,4-diazabicyclo[2.2.H3C H DMA, 100 °C, 5 h 2]octane (DABCO), triethoxymethane,CH 3 and dimethylacetamide afforded the desired product of evodiamine (Scheme 15). 71% yield 48 84 An indole based alkaloid, Eudistomin K isolated from the Caribbean Evodiamineascidian Eudistoma olivaceum was found to be potent against human lung cancer (A-549) cell lines. It is reported to inhibit Scheme 15. SynthesisSynthesis of of evodiamine evodiamine adap adaptedted from the reference [[114].114]. the P-388 tumor cell line with IC50 of 0.01 μg/mL (Figure 13) [115]. Evodiamine was synthesized as shown in Scheme 15[ 114]. The reaction of tryptamine (48) with EvodiamineBisindolylalkanes was synthesized comprise two as shown monomeric in Sche indoleme 15 alkaloid [114]. The units, reaction derived of tryptamine from several (48 natural) with N-methylisatoic anhydride (84) in the presence of trifluoroacetic anhydride, 1,4-diazabicyclo[2.2. N-methylisatoicterrestrial and marine anhydride sources. (84) They in the are presence known fo ofr theirtrifluoroacetic biological, anhydride, pharmacological, 1,4-diazabicyclo[2.2. and medicinal 2]octane (DABCO), triethoxymethane, and dimethylacetamide afforded the desired product of 2]octaneproperties. (DABCO), Villalstonine triethoxymet is derivedhane, from and the dimethylacetamide Alstonia species, whichafforded is commonlythe desired found product in theof evodiamine (Scheme 15). evodiaminetropical and (Scheme subtropical 15). regions. It was evaluated for its anti-cancer activity against human NSCLC An indole based alkaloid, Eudistomin K isolated from the Caribbean ascidian Eudistoma olivaceum cell lines,An indole adenocarcinoma based alkaloid, (MOR-P), Eudistomin and large K cell isolated carcinoma from (COR-L23) the Caribbean cell lines. ascidian Villalstonine Eudistoma was was found to be potent against human lung cancer (A-549) cell lines. It is reported to inhibit the P-388 olivaceumdemonstrated was found to be topotent be potent in cytotoxic against humanactivity lungwith cancer IC50 of (A-549) 5 μM and cell 2.5lines. μM It isin reportedMOR-P andto inhibit COR- tumorL23 cells, cell respectively line with IC50 (Figureof 0.01 13)µg [116]./mL (Figure 13)[115]. the P-388 tumor cell line with IC50 of 0.01 μg/mL (Figure 13) [115]. Bisindolylalkanes comprise two monomeric units, derived from several natural terrestrial and marine sources. They are known for their biological, pharmacological, and medicinal properties. Villalstonine is derived from the Alstonia species, which is commonly found in the tropical and subtropical regions. It was evaluated for its anti-cancer activity against human NSCLC cell lines, adenocarcinoma (MOR-P), and large cell carcinoma (COR-L23) cell lines. Villalstonine was demonstrated to be potent in cytotoxic activity with IC50 of 5 μM and 2.5 μM in MOR-P and COR- L23 cells, respectively (Figure 13) [116].

FigureFigure 13.13.Structures Structures ofof eudistomineudistomin K,K,villalstonine, villalstonine, compounds compounds85 85,,86 86and and87 87..

Bisindolylalkanes comprise two monomeric indole alkaloid units, derived from several natural terrestrial and marine sources. They are known for their biological, pharmacological, and medicinal properties. Villalstonine is derived from the Alstonia species, which is commonly found in the tropical and subtropical regions. It was evaluated for its anti-cancer activity against human NSCLC cell lines, adenocarcinoma (MOR-P), and large cell carcinoma (COR-L23) cell lines. Villalstonine was demonstrated to be potent in cytotoxic activity with IC50 of 5 µM and 2.5 µM in MOR-P and COR-L23 cells, respectivelyFigure (Figure 13. Structures 13)[116]. of eudistomin K, villalstonine, compounds 85, 86 and 87. Ji et al. reported a novel class of indole-2-carboxylate derivatives, evaluating their anti-cancer activity. They found that some compounds exhibited excellent anti-proliferative activity against HepG2, A549, and MCF7 cells. Most importantly, compounds 85 and 86 showed more potency than etoposide and pyrroloquinoline quinone drugs with IC50 ranging from 3.4 to 24 µM (Figure 13). When compounds 85 and 86 were subjected to a Western blot analysis of poly ADP ribose polymerase (PARP), both compounds triggered ROS production and induced PARP cleavage in A549 cells. This study was done in a dose-dependent manner, indicating the induction of apoptosis. The results showed that these substances can be promising lead compounds for the development of anti-lung cancer drugs [117]. Molecules 2020, 25, 1615 19 of 25

Skouta et al. designed and synthesized a series of tetrahydro-β-carbolines derivatives. These compounds were tested for their efficacy against a variety of human cancer cell lines, including the lung cancer cells (H1299). They found that derivatives of tetrahydro-ß-carboline and barbituric acid moieties with no spacer showed modest activity with LC50 of 32.8 µM in the H1299 cell lines. Those analogs with a carbon spacer were either weakly active or non-selective. Compound 87 was found to be the most potent than any of the derivatives. It was observed to induce caspase-independent cell death selectively in cancerous cells [118].

3. Conclusions Overall, indole based compounds have emerged as a powerful probe for scientists in the ongoing battle against such life-threatening diseases, such as lung cancer. Significant advances in this area are evidenced in the number of indole-based compounds entering the pre-clinical and clinical stages. More advances are expected to meet the challenges associated with the accompanying chemotherapy. With a better understanding of the drug resistance mechanism in lung cancer patients, coupled with the multi-drug therapy advances offered by the indole-based derivatives, better and more promising strategies for combatting lung cancer can be expected in the near future.

Author Contributions: Conceptualization, J.D. and R.S.; Methodology, n/a; Software, n/a.; Validation, n/a.; Formal Analysis, n/a; Investigation, n/a; Resources, n/a.; Data Curation, n/a.; Writing-Original Draft Preparation, J.D.; Writing-Review & Editing, J.D. and R.S.; Visualization, J.D. and R.S.; Supervision, R.S.; Project Administration, n/a.; Funding Acquisition, R.S. All authors have read and agreed to the published version of the manuscript. Funding: This specific review received no external funding. Acknowledgments: The authors thank: (i) Lung Cancer Research Foundation, (ii) the Department of Chemistry, and (iii) the Department Biology at the University of Massachusetts (UMASS) for financial support. Conflicts of Interest: The authors declare no conflict of interest.

References

1. Bray, F.; Ferlay, J.; Soerjomataram, I. Global. GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries, CA. Cancer J. Clin. 2018, 68, 394–424. [CrossRef][PubMed] 2. Goldstraw, P.; Chansky, K.; Crowley, J.; Rami-Porta, R.; Asamura, H.; Eberhardt, W.E.E.; Nicholson, A.G.; Groome, P.; Mitchell, A.; Bolejack, V.; et al. The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer. J. Thorac. Oncol. 2016, 11, 39–51. [CrossRef][PubMed] 3. Jones, G.S.; Baldwin, D.R. Recent Advances in the Management of Lung Cancer. Clin. Med. Lond. Engl. 2018, 18, s41–s46. [CrossRef] 4. Hakim, M.; Broza, Y.Y.; Barash, O.; Peled, N.; Phillips, M.; Amann, A.; Haick, H. Volatile Organic Compounds of Lung Cancer and Possible Biochemical Pathways. Chem. Rev. 2012, 112, 5949–5966. [CrossRef][PubMed] 5. Mohammadi Ziarani, G.; Moradi, R.; Ahmadi, T.; Lashgari, N. Recent Advances in the Application of Indoles in Multicomponent Reactions. RSC Adv. 2018, 8, 12069–12103. [CrossRef] 6. Sundberg, R.J. Electrophilic Substitution Reactions of Indoles. In Heterocyclic Scaffolds II: Reactions and Applications of Indoles; Gribble, G.W., Ed.; Springer: Berlin/Heidelberg, Germany, 2010; pp. 47–115. [CrossRef] 7. Baeyer, A.; Emmerling, A. Synthese des Indols. Berichte Dtsch. Chem. Ges. 1869, 2, 679–682. [CrossRef] 8. Fischer, E.; Hess, O. Synthese von Indolderivaten. Berichte Dtsch. Chem. Ges. 1884, 17, 559–568. [CrossRef] 9. Bischler, A.; Napieralski, B. Zur Kenntniss einer neuen Isochinolinsynthese. Berichte Dtsch. Chem. Ges. 1893, 26, 1903–1908. [CrossRef] 10. Hemetsberger, H.; Knittel, D. Synthese und Thermolyse von α-Azidoacrylestern. Mon. Fur Chem. 1972, 103, 194–204. [CrossRef] 11. Nenitzescu, C.D. Derivatives of 2-Methyl-5-Hydroxyindole. Bull. Soc. Chim. Rom. 1929, 11, 37–43. 12. Bartoli, G.; Palmieri, G.; Bosco, M.; Dalpozzo, R. The Reaction of Vinyl Grignard Reagents with 2-Substituted Nitroarenes: A New Approach to the Synthesis of 7-Substituted Indoles. Tetrahedron Lett. 1989, 30, 2129–2132. [CrossRef] Molecules 2020, 25, 1615 20 of 25

13. Yamagishi, M.; Nishigai, K.; Ishii, A.; Hata, T.; Urabe, H. Facile Preparation of Indoles and 1,2-Benzothiazine 1,1-Dioxides: Nucleophilic Addition of Sulfonamides to Bromoacetylenes and Subsequent Palladium-Catalyzed Cyclization. Angew. Chem. Int. Ed. 2012, 51, 6471–6474. [CrossRef][PubMed] 14. Tan, Y.; Hartwig, J.F. Palladium-Catalyzed Amination of Aromatic C H Bonds with Oxime Esters. J. Am. − Chem. Soc. 2010, 132, 3676–3677. [CrossRef][PubMed] 15. Li Petri, G.; Cascioferro, S.; El Hassouni, B.; Carbone, D.; Parrino, B.; Cirrincione, G.; Peters, G.J.; Diana, P.; Giovannetti, E. Biological Evaluation of the Antiproliferative and Anti-Migratory Activity of a Series of 3-(6-Phenylimidazo[2,1-b][1,3,4]Thiadiazol-2-Yl)-1 H -Indole Derivatives Against Pancreatic Cancer Cells. Anticancer Res. 2019, 39, 3615–3620. [CrossRef] 16. Cascioferro, S.; Attanzio, A.; Di Sarno, V.; Musella, S.; Tesoriere, L.; Cirrincione, G.; Diana, P.; Parrino, B. New 1,2,4-Oxadiazole Nortopsentin Derivatives with Cytotoxic Activity. Mar. Drugs 2019, 17, 35. [CrossRef] 17. Carbone, A.; Parrino, B.; Cusimano, M.; Spanò, V.; Montalbano, A.; Barraja, P.; Schillaci, D.; Cirrincione, G.; Diana, P.; Cascioferro, S. New Nortopsentin Analogues Inhibit Bacterial Biofilm Formation. Mar. Drugs 2018, 16, 274. [CrossRef] 18. Higdon, J.; Delage, B.; Williams, D.; Dashwood, R. Cruciferous Vegetables and Human Cancer Risk: Epidemiologic Evidence and Mechanistic Basis. Pharmacol. Res. 2007, 55, 224–236. [CrossRef] 19. Hornedo-Ortega, R.; Da Costa, G.; Cerezo, A.B.; Troncoso, A.M.; Richard, T.; Garcia-Parrilla, M.C. In Vitro Effects of Serotonin, Melatonin, and Other Related Indole Compounds on Amyloid-β Kinetics and Neuroprotection. Mol. Nutr. Food Res. 2018, 62, 1700383. [CrossRef] 20. Palmieri, A.; Petrini, M. and Derivatives: Natural Occurrence and Applications to the Synthesis of Bioactive Compounds. Nat. Prod. Rep. 2019, 36, 490–530. [CrossRef] 21. Fu, S.-F.; Wei, J.-Y.; Chen, H.-W.; Liu, Y.-Y.; Lu, H.-Y.; Chou, J.-Y. Indole-3-Acetic Acid: A Widespread Physiological Code in Interactions of Fungi with Other Organisms. Plant Signal. Behav. 2015, 10, e1048052. [CrossRef] 22. Sun, H.; Sun, W.; Zhang, A.; Wang, X. Metabolite Profiling and Biomarkers Analysis of Jaundice Syndrome-Related Animal Models. In Chinmedomics; Elsevier: Boston, MA, USA, 2015; pp. 109–145. [CrossRef] 23. Delavirdine Gets FDA Approval. Food and Drug Administration. AIDS Alert 1997, 12, 70. 24. Lobay, D. Rauwolfia in the Treatment of Hypertension. Integr. Med. Encinitas Calif. 2015, 14, 40–46. 25. Yee, A.J.; Raje, N.S. Panobinostat and Multiple Myeloma in 2018. Oncologist 2018, 23, 516–517. [CrossRef] [PubMed] 26. Rasmussen, T.A.; Tolstrup, M.; Brinkmann, C.R.; Olesen, R.; Erikstrup, C.; Solomon, A.; Winckelmann, A.; Palmer, S.; Dinarello, C.; Buzon, M.; et al. Panobinostat, a Histone Deacetylase Inhibitor, for Latent- Reactivation in HIV-Infected Patients on Suppressive Antiretroviral Therapy: A Phase 1/2, Single Group, Clinical Trial. Lancet HIV 2014, 1, e13–e21. [CrossRef] 27. Kelloway, J.S. Zafirlukast: The First Leukotreene-Receptor Antagonist Approved for the Treatment of Asthma. Ann. Pharmacother. 1997, 31, 1012–1021. [CrossRef][PubMed] 28. Frajese, G.V.; Pozzi, F.; Frajese, G. Tadalafil in the Treatment of Erectile Dysfunction; an Overview of the Clinical Evidence. Clin. Interv. Aging 2006, 1, 439–449. [CrossRef][PubMed] 29. Liu, Y.; Zhou, X.; Zhu, D.; Chen, J.; Qin, B.; Zhang, Y.; Wang, X.; Yang, D.; Meng, H.; Luo, Q.; et al. Is Pindolol Augmentation Effective in Depressed Patients Resistant to Selective Serotonin Reuptake Inhibitors? A Systematic Review and Meta-Analysis: PINDOLOL IN SSRI-RESISTANT DEPRESSION. Hum. Psychopharmacol. Clin. Exp. 2015, 30, 132–142. [CrossRef][PubMed] 30. Blier, P.; Bergeron, R. The Use of Pindolol to Potentiate Antidepressant . J. Clin. Psychiatry 1998, 59, 16–23, discussion 24-5. 31. Ferreira, S.H.; Moncada, S.; Vane, J.R. Indomethacin and Aspirin Abolish Prostaglandin Release from the Spleen. Nat. New Biol. 1971, 231, 237–239. [CrossRef] 32. Heijden, R.; Jacobs, D.; Snoeijer, W.; Hallard, D.; Verpoorte, R. The Catharanthus Alkaloids:Pharmacognosy and Biotechnology. Curr. Med. Chem. 2004, 11, 607–628. [CrossRef] 33. Zhang, Y.; Yang, S.-H.; Guo, X.-L. New Insights into Vinca Alkaloids Resistance Mechanism and Circumvention in Lung Cancer. Biomed. Pharm. Biomed. Pharm. 2017, 96, 659–666. [CrossRef][PubMed] Molecules 2020, 25, 1615 21 of 25

34. Tomasini, P.; Egea, J.; Souquet-Bressand, M.; Greillier, L.; Barlesi, F. Alectinib in the Treatment of ALK-Positive Metastatic Non-Small Cell Lung Cancer: Clinical Trial Evidence and Experience with a Focus on Brain Metastases. Ther. Adv. Respir. Dis. 2019, 13.[CrossRef][PubMed] 35. Le Tourneau, C.; Raymond, E.; Faivre, S. Sunitinib: A Novel Tyrosine Kinase Inhibitor. A Brief Review of Its Therapeutic Potential in the Treatment of Renal Carcinoma and Gastrointestinal Stromal Tumors (GIST). Ther. Clin. Risk Manag. 2007, 3, 341–348. [CrossRef] 36. Greig, S.L. Osimertinib: First Global Approval. Drugs 2016, 76, 263–273. [CrossRef][PubMed] 37. Mishra, D.P.; Khan, M.A.; Yadav, D.K.; Rawat, A.K.; Singh, R.K.; Ahamad, T.; Hussain, M.K.; Saquib, M.; Khan, M.F. Indole Alkaloids from Anthocephalus Cadamba Fruits Exhibiting Anticancer Activity in Human Lung Cancer Cell Line H1299. Chem. Sel. 2018, 3, 8468–8472. [CrossRef] 38. Shao, L.; Wang, W.; Song, Z.; Zhang, Y. The Efficacy and Safety of Anlotinib Treatment for Advanced Lung Cancer. Onco Targets Ther. 2019, 12, 6549–6554. [CrossRef] 39. Dadashpour, S.; Emami, S. Indole in the Target-Based Design of Anticancer Agents: A Versatile Scaffold with Diverse Mechanisms. Eur. J. Med. Chem. 2018, 150, 9–29. [CrossRef] 40. Leoni, A.; Locatelli, A.; Morigi, R.; Rambaldi, M. 2-Indolinone a Versatile Scaffold for Treatment of Cancer: A Patent Review (2008–2014). Expert Opin. Ther. Pat. 2016, 26, 149–173. [CrossRef] 41. Kumar, N.M.; Kumar, D. Recent Developments on Synthetic Indoles as Potent Anticancer Agents. Chem. Biol. Interface 2013, 3, 276–303. 42. De Sa Alves, F.; Barreiro, E.; Manssour Fraga, C. From nature to drug discovery: The indole scaffold as a ‘privileged structure. Mini-Rev. Med. Chem. 2009, 9, 782–793. [CrossRef] 43. Sravanthi, T.V.; Manju, S.L. Indoles—A Promising Scaffold for Drug Development. Eur. J. Pharm. Sci. 2016, 91, 1–10. [CrossRef][PubMed] 44. Kaushik, N.; Kaushik, N.; Attri, P.; Kumar, N.; Kim, C.; Verma, A.; Choi, E. Biomedical Importance of Indoles. Molecules 2013, 18, 6620–6662. [CrossRef][PubMed] 45. Sunil, D.; Kamath, P.Multi-Target Directed Indole Based Hybrid Molecules in Cancer Therapy: An Up-To-Date Evidence-Based Review. Curr. Top. Med. Chem. 2017, 17, 959–985. [CrossRef][PubMed] 46. Chadha, N.; Silakari, O. Indoles as Therapeutics of Interest in Medicinal Chemistry: Bird’s Eye View. Eur. J. Med. Chem. 2017, 134, 159–184. [CrossRef][PubMed] 47. El-sayed, M.T.; Hamdy, N.A.; Osman, D.A.; Ahmed, K.M. Indoles as Anticancer Agents. Adv. Mod. Oncol. Res. 2015, 1, 20. [CrossRef] 48. Nicholson, R.I.; Gee, J.M.W.; Harper, M.E. EGFR and Cancer Prognosis. Eur. J. Cancer 2001, 37, 9–15. [CrossRef] 49. Engelman, J.A. The Role of Phosphoinositide 3-Kinase Pathway Inhibitors in the Treatment of Lung Cancer. Clin. Cancer Res. 2007, 13, 4637s–4640s. [CrossRef] 50. Brognard, J.; Clark, A.S.; Ni, Y.; Dennis, P.A. Akt/Protein Kinase B Is Constitutively Active in Non-Small Cell Lung Cancer Cells and Promotes Cellular Survival and Resistance to Chemotherapy and Radiation. Cancer Res. 2001, 61, 3986–3997. 51. Hemmings, B.A.; Restuccia, D.F. PI3K-PKB/Akt Pathway. Cold Spring Harb. Perspect. Biol. 2012, 4, a011189. [CrossRef] 52. Altomare, D.A.; Testa, J.R. Perturbations of the AKT Signaling Pathway in Human Cancer. Oncogene 2005, 24, 7455–7464. [CrossRef] 53. Cheng, H.; Shcherba, M.; Pendurti, G.; Liang, Y.; Piperdi, B.; Perez-Soler, R. Targeting the PI3K/AKT/MTOR Pathway: Potential for Lung Cancer Treatment. Lung Cancer Manag. 2014, 3, 67–75. [CrossRef][PubMed] 54. Guo, Y.; Du, J.; Kwiatkowski, D.J. Molecular Dissection of AKT Activation in Lung Cancer Cell Lines. Mol. Cancer Res. 2013, 11, 282–293. [CrossRef][PubMed] 55. Nesi, G.; Sestito, S.; Mey, V.; Ricciardi, S.; Falasca, M.; Danesi, R.; Lapucci, A.; Breschi, M.C.; Fogli, S.; Rapposelli, S. Synthesis of Novel 3,5-Disubstituted-2-Oxindole Derivatives As Antitumor Agents against Human Nonsmall Cell Lung Cancer. ACS Med. Chem. Lett. 2013, 4, 1137–1141. [CrossRef][PubMed] 56. Zhao, B.; Xiao, Z.; Qi, J.; Luo, R.; Lan, Z.; Zhang, Y.; Hu, X.; Tang, Q.; Zheng, P.; Xu, S.; et al. Design, Synthesis and Biological Evaluation of AZD9291 Derivatives as Selective and Potent EGFRL858R/T790M Inhibitors. Eur. J. Med. Chem. 2019, 163, 367–380. [CrossRef] Molecules 2020, 25, 1615 22 of 25

57. Sam, B.; Maurice, R.V.F.; Richard, A.W.; Vasantha, K.K.; Reddy, C.C.; Andiappan, M.; Heather, M.R. 2-(2,4,5-Substituted Anilino)Pyrimidine Derivatives as EGFR Modulators Useful for Treating Cancer. WO2013014448A1, 31 January 2013. 58. Wang, Y.; Wang, L.; Guan, S.; Cao, W.; Wang, H.; Chen, Z.; Zhao, Y.; Yu, Y.; Zhang, H.; Pang, J.C.; et al. Novel ALK Inhibitor AZD3463 Inhibits Neuroblastoma Growth by Overcoming Crizotinib Resistance and Inducing Apoptosis. Sci. Rep. 2016, 6, 19423. [CrossRef] 59. Soda, M.; Choi, Y.L.; Enomoto, M.; Takada, S.; Yamashita, Y.; Ishikawa, S.; Fujiwara, S.; Watanabe, H.; Kurashina, K.; Hatanaka, H.; et al. Identification of the Transforming EML4–ALK Fusion Gene in Non-Small-Cell Lung Cancer. Nature 2007, 448, 561–566. [CrossRef] 60. Kinoshita, K.; Asoh, K.; Furuichi, N.; Ito, T.; Kawada, H.; Hara, S.; Ohwada, J.; Miyagi, T.; Kobayashi, T.; Takanashi, K.; et al. Design and Synthesis of a Highly Selective, Orally Active and Potent Anaplastic Lymphoma Kinase Inhibitor (CH5424802). Bioorg. Med. Chem. 2012, 20, 1271–1280. [CrossRef] 61. Kinoshita, K.; Kobayashi, T.; Asoh, K.; Furuichi, N.; Ito, T.; Kawada, H.; Hara, S.; Ohwada, J.; Hattori, K.; Miyagi, T.; et al. 9-Substituted 6,6-Dimethyl-11-Oxo-6,11-Dihydro-5 H -Benzo[ b ] as Highly Selective and Potent Anaplastic Lymphoma Kinase Inhibitors. J. Med. Chem. 2011, 54, 6286–6294. [CrossRef] 62. Newton, A.C. Protein Kinase C: Structure, Function, and Regulation. J. Biol. Chem. 1995, 270, 28495–28498. [CrossRef] 63. Herbst, R.S.; Oh, Y.; Wagle, A.; Lahn, M. Enzastaurin, a Protein Kinase C Selective Inhibitor, and Its Potential Application as an Anticancer Agent in Lung Cancer. Clin. Cancer Res. 2007, 13, 4641s–4646s. [CrossRef] 64. Ann, M.M.; Bruce, W.K.; Rebecca, L.L.; Donald, T.; Larry, D.; Bruce, C.; Julia, H.C.; Jeremy, R.G. Enzastaurin (LY317615.HCl) Suppresses Signaling through the PKC and AKT Pathways, Inducing Apoptosis, Suppressing Tumor-Induced Angiogenesis and Reducing Growth of Human Cancer Xenografts. Cancer Res. 2006, 66, 314–315. 65. Nakajima, E.; Helfrich, B.; Chan, D.; Zhang, Z.; Hirsch, F.R.; Chen, V.; Ma, D.; Bunn, P.A. Enzastaurin a Protein Kinase Cbeta-Selective Inhibitor, Inhibits the Growth of SCLC and NSCLC Cell Lines. J. Clin. Oncol. 2006, 24, 13138. [CrossRef] 66. Crump, M.; Leppä, S.; Fayad, L.; Lee, J.J.; Di Rocco, A.; Ogura, M.; Hagberg, H.; Schnell, F.; Rifkin, R.; Mackensen, A.; et al. Randomized, Double-Blind, Phase III Trial of Enzastaurin Versus Placebo in Patients Achieving Remission After First-Line Therapy for High-Risk Diffuse Large B-Cell Lymphoma. J. Clin. Oncol. 2016, 34, 2484–2492. [CrossRef][PubMed] 67. Wang, M.; Xu, L.; Gao, M.; Miller, K.D.; Sledge, G.W.; Zheng, Q.-H. [11C]Enzastaurin, the First Design and Radiosynthesis of a New Potential PET Agent for Imaging of Protein Kinase, C. Bioorg. Med. Chem. Lett. 2011, 21, 1649–1653. [CrossRef] 68. Remsing Rix, L.L.; Kuenzi, B.M.; Luo, Y.; Remily-Wood, E.; Kinose, F.; Wright, G.; Li, J.; Koomen, J.M.; Haura, E.B.; Lawrence, H.R.; et al. GSK3 Alpha and Beta Are New Functionally Relevant Targets of Tivantinib in Lung Cancer Cells. ACS Chem. Biol. 2014, 9, 353–358. [CrossRef] 69. Scagliotti, G.V.; Shuster, D.; Orlov, S.; von Pawel, J.; Shepherd, F.A.; Ross, J.S.; Wang, Q.; Schwartz, B.; Akerley, W. Tivantinib in Combination with Erlotinib versus Erlotinib Alone for EGFR-Mutant NSCLC: An Exploratory Analysis of the Phase 3 MARQUEE Study. J. Thorac. Oncol. 2018, 13, 849–854. [CrossRef] 70. Li, C.J.; Ashwell, M.A.; Hill, J.; Moussa, M.M.; Munshi, N. Maleimide Derivatives, Pharmaceutical Compositions and Methods for Treatment of Cancer. EP1846406B9, 11 January 2012. 71. Lin, B.; Song, X.; Yang, D.; Bai, D.; Yao, Y.; Lu, N. Anlotinib Inhibits Angiogenesis via Suppressing the Activation of VEGFR2, PDGFRβ and FGFR1. Gene 2018, 654, 77–86. [CrossRef] 72. Cheng, Y.; Wang, Q.; Li, K.; Shi, J.; Liu, Y.; Wu, L.; Han, B.; Chen, G.; He, J.; Wang, J.; et al. 1738OOverall Survival (OS) Update in ALTER 1202: Anlotinib as Third-Line or Further-Line Treatment in Relapsed Small-Cell Lung Cancer (SCLC). Ann. Oncol. 2019, 30.[CrossRef] 73. Reck, M.; Mellemgaard, A.; Novello, S.; Postmus, P.E.; Gaschler-Markefski, B.; Kaiser, R.; Buchner, H. Change in Non-Small-Cell Lung Cancer Tumor Size in Patients Treated with Nintedanib plus Docetaxel: Analyses from the Phase III LUME-Lung 1 Study. OncoTargets Ther. 2018, 11, 4573–4582. [CrossRef] 74. Corrales, L.; Nogueira, A.; Passiglia, F.; Listi, A.; Caglevic, C.; Giallombardo, M.; Raez, L.; Santos, E.; Rolfo, C. Second-Line Treatment of Non-Small Cell Lung Cancer: Clinical, Pathological, and Molecular Aspects of Nintedanib. Front. Med. 2017, 4.[CrossRef] 75. Fletcher, D.A.; Mullins, R.D. Cell Mechanics and the Cytoskeleton. Nature 2010, 463, 485–492. [CrossRef] Molecules 2020, 25, 1615 23 of 25

76. Naaz, F.; Haider, M.R.; Shafi, S.; Yar, M.S. Anti-Tubulin Agents of Natural Origin: Targeting Taxol, Vinca, and Colchicine Binding Domains. Eur. J. Med. Chem. 2019, 171, 310–331. [CrossRef][PubMed] 77. Adam, Z.; Coupková, H.; Kolek, V.; Kucera, M.; Loffelmann, L.; Martinez, A.; Nováková, M.; Pr ˚usa,P.; Reiterer, P.; Skalová, B. Vinorelbine and Cisplatin in the Treatment of Advanced Non-Small Cell Lung Cancer: Results of a Multicenter Czech Study. Acta Med. Austriaca 1995, 22, 120–124. [PubMed] 78. Genova, C.; Alama, A.; Coco, S.; Rijavec, E.; Dal Bello, M.G.; Vanni, I.; Biello, F.; Barletta, G.; Rossi, G.; Grossi, F. Vinflunine for the Treatment of Non-Small Cell Lung Cancer. Expert Opin. Investig. Drugs 2016, 25, 1447–1455. [CrossRef][PubMed] 79. Cong, H.; Zhao, X.; Castle, B.T.; Pomeroy, E.J.; Zhou, B.; Lee, J.; Wang, Y.; Bian, T.; Miao, Z.; Zhang, W.; et al. An Indole–Chalcone Inhibits Multidrug-Resistant Cancer Cell Growth by Targeting Microtubules. Mol. Pharm. 2018, 15, 3892–3900. [CrossRef][PubMed] 80. Das Mukherjee, D.; Kumar, N.M.; Tantak, M.P.; Das, A.; Ganguli, A.; Datta, S.; Kumar, D.; Chakrabarti, G. Development of Novel Bis(Indolyl)-Hydrazide–Hydrazone Derivatives as Potent Microtubule-Targeting Cytotoxic Agents against A549 Lung Cancer Cells. 2016, 55, 3020–3035. [CrossRef][PubMed] 81. Chaniyara, R.; Tala, S.; Chen, C.-W.; Zang, X.; Kakadiya, R.; Lin, L.-F.; Chen, C.-H.; Chien, S.-I.; Chou, T.-C.; Tsai, T.-H.; et al. Novel Antitumor Indolizino[6,7- b ]Indoles with Multiple Modes of Action: DNA Cross-Linking and Topoisomerase I and II Inhibition. J. Med. Chem. 2013, 56, 1544–1563. [CrossRef] [PubMed] 82. Chen, C.-W.; Wu, M.-H.; Chen, Y.-F.; Yen, T.-Y.; Lin, Y.-W.; Chao, S.-H.; Tala, S.; Tsai, T.-H.; Su, T.-L.; Lee, T.-C. A Potent Derivative of Indolizino[6,7-b]Indole for Treatment of Human Non–Small Cell Lung Cancer Cells. Neoplasia 2016, 18, 199–212. [CrossRef] 83. Chang, S.-M.; Christian, W.; Wu, M.-H.; Chen, T.-L.; Lin, Y.-W.; Suen, C.-S.; Pidugu, H.B.; Detroja, D.; Shah, A.; Hwang, M.-J.; et al. Novel Indolizino[8,7-b]Indole Hybrids as Anti-Small Cell Lung Cancer Agents: Regioselective Modulation of Topoisomerase II Inhibitory and DNA Crosslinking Activities. Eur. J. Med. Chem. 2017, 127, 235–249. [CrossRef] 84. Song, Y.-L.; Dong, Y.-F.; Yang, T.; Zhang, C.-C.; Su, L.-M.; Huang, X.; Zhang, D.-N.; Yang, G.-L.; Liu, Y.-X. Synthesis and Pharmacological Evaluation of Novel Bisindolylalkanes Analogues. Bioorg. Med. Chem. 2013, 21, 7624–7627. [CrossRef] 85. Barrows, L.R.; Radisky, D.C.; Copp, B.R.; Swaffar, D.S.; Kramer, R.A.; Warters, R.L.; Ireland, C.M. Makaluvamines, Marine Natural Products, Are Active Anti-Cancer Agents and DNA Topo II Inhibitors. Anticancer Drug Des. 1993, 8, 333–347. [PubMed] 86. Nadkarni, D.; Wang, F.; Wang, W.; Rayburn, E.; Ezell, S.; Murugesan, S.; Velu, S.; Zhang, R. Synthesis and In Vitro Anti-Lung Cancer Activity of Novel 1, 3, 4, 8- Tetrahydropyrrolo [4, 3, 2-de]Quinolin-8(1H)-o Ne Alkaloid Analogs. Med. Chem. 2009, 5, 227–236. [CrossRef][PubMed] 87. Lane, A.A.; Chabner, B.A. Histone Deacetylase Inhibitors in Cancer Therapy. J. Clin. Oncol. 2009, 27, 5459–5468. [CrossRef][PubMed] 88. Richon, V.M.; O’Brien, J.P. Histone Deacetylase Inhibitors: A New Class of Potential Therapeutic Agents for Cancer Treatment. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2002, 8, 662–664. 89. Johnstone, R.W. Histone-Deacetylase Inhibitors: Novel Drugs for the Treatment of Cancer. Nat. Rev. Drug Discov. 2002, 1, 287–299. [CrossRef] 90. Shinji, C.; Maeda, S.; Imai, K.; Yoshida, M.; Hashimoto, Y.; Miyachi, H. Design, Synthesis, and Evaluation of Cyclic Amide/Imide-Bearing Hydroxamic Acid Derivatives as Class-Selective Histone Deacetylase (HDAC) Inhibitors. Bioorg. Med. Chem. 2006, 14, 7625–7651. [CrossRef] 91. Han, S.; Fukazawa, T.; Yamatsuji, T.; Matsuoka, J.; Miyachi, H.; Maeda, Y.; Durbin, M.; Naomoto, Y. Anti-Tumor Effect in Human Lung Cancer by a Combination Treatment of Novel Histone Deacetylase Inhibitors: SL142 or SL325 and Retinoic Acids. PLoS ONE 2010, 5, e13834. [CrossRef] 92. Lai, M.-J.; Huang, H.-L.; Pan, S.-L.; Liu, Y.-M.; Peng, C.-Y.; Lee, H.-Y.; Yeh, T.-K.; Huang, P.-H.; Teng, C.-M.; Chen, C.-S.; et al. Synthesis and Biological Evaluation of 1-Arylsulfonyl-5-(N-Hydroxyacrylamide)Indoles as Potent Histone Deacetylase Inhibitors with Antitumor Activity in Vivo. J. Med. Chem. 2012, 55, 3777–3791. [CrossRef] Molecules 2020, 25, 1615 24 of 25

93. Remiszewski, S.W.; Sambucetti, L.C.; Bair, K.W.; Bontempo, J.; Cesarz, D.; Chandramouli, N.; Chen, R.; Cheung, M.; Cornell-Kennon, S.; Dean, K.; et al. N -Hydroxy-3-Phenyl-2-Propenamides as Novel Inhibitors of Human Histone Deacetylase with in Vivo Antitumor Activity: Discovery of (2 E)- N -Hydroxy-3-[4-[[(2-Hydroxyethyl)[2-(1 H -Indol-3-Yl)Ethyl]Amino]Methyl]Phenyl]-2-Propenamide (NVP-LAQ824). J. Med. Chem. 2003, 46, 4609–4624. [CrossRef] 94. Catley, L.; Weisberg, E.; Tai, Y.-T.; Atadja, P.; Remiszewski, S.; Hideshima, T.; Mitsiades, N.; Shringarpure, R.; LeBlanc, R.; Chauhan, D.; et al. NVP-LAQ824 Is a Potent Novel Histone Deacetylase Inhibitor with Significant Activity against Multiple Myeloma. Blood 2003, 102, 2615–2622. [CrossRef] 95. Atadja, P.; Gao, L.; Kwon, P.; Trogani, N.; Walker, H.; Hsu, M.; Yeleswarapu, L.; Chandramouli, N.; Perez, L.; Versace, R.; et al. Selective Growth Inhibition of Tumor Cells by a Novel Histone Deacetylase Inhibitor, NVP-LAQ824. Cancer Res. 2004, 64, 689–695. [CrossRef] 96. Cuneo, K.C.; Fu, A.; Osusky, K.; Huamani, J.; Hallahan, D.E.; Geng, L. Histone Deacetylase Inhibitor NVP-LAQ824 Sensitizes Human Nonsmall Cell Lung Cancer to the Cytotoxic Effects of Ionizing Radiation: Anticancer. Drugs 2007, 18, 793–800. [CrossRef][PubMed] 97. Ellis, L.; Bots, M.; Lindemann, R.K.; Bolden, J.E.; Newbold, A.; Cluse, L.A.; Scott, C.L.; Strasser, A.; Atadja, P.; Lowe, S.W.; et al. The Histone Deacetylase Inhibitors LAQ824 and LBH589 Do Not Require Death Receptor Signaling or a Functional Apoptosome to Mediate Tumor Cell Death or Therapeutic Efficacy. Blood 2009, 114, 380–393. [CrossRef][PubMed] 98. Remiszewski, S.W. The Discovery of NVP-LAQ824: From Concept to Clinic. Curr. Med. Chem. 2003, 10, 2393–2402. [CrossRef][PubMed] 99. Lv, K.; Wang, L.-L.; Zhou, X.-B.; Liu, M.-L.; Liu, H.-Y.; Zheng, Z.-B.; Li, S. Synthesis and in Vitro Antitumor Activity of 1-(3-Dimethylamino)Propyl Indolin-2-One Derivatives. Med. Chem. Res. 2013, 22, 1723–1729. [CrossRef] 100. Lv, K.; Wang, L.-L.; Liu, M.-L.; Zhou, X.-B.; Fan, S.-Y.; Liu, H.-Y.; Zheng, Z.-B.; Li, S. Synthesis and Antitumor Activity of 5-[1-(3-(Dimethylamino)Propyl)-5-Halogenated-2-Oxoindolin-(3Z)-Ylidenemethyl]- 2,4-Dimethyl-1H-Pyrrole-3-Carboxamides. Bioorg. Med. Chem. Lett. 2011, 21, 3062–3065. [CrossRef] [PubMed] 101. Kohmoto, S.; Kashman, Y.; McConnell, O.J.; Rinehart, K.L.; Wright, A.; Koehn, F. Dragmacidin, a New Cytotoxic Bis(Indole) Alkaloid from a Deep Water Marine Sponge, Dragmacidon sp. J. Org. Chem. 1988, 53, 3116–3118. [CrossRef] 102. Zhao, X.; Dong, W.; Gao, Y.; Shin, D.-S.; Ye, Q.; Su, L.; Jiang, F.; Zhao, B.; Miao, J. Novel Indolyl-Chalcone Derivatives Inhibit A549 Lung Cancer Cell Growth through Activating Nrf-2/HO-1 and Inducing Apoptosis in Vitro and in Vivo. Sci. Rep. 2017, 7, 3919. [CrossRef] 103. Hu, H.; Wu, J.; Ao, M.; Wang, H.; Zhou, T.; Xue, Y.; Qiu, Y.; Fang, M.; Wu, Z. Synthesis, Structure-Activity Relationship Studies and Biological Evaluation of Novel 2,5-Disubstituted Indole Derivatives as Anticancer Agents. Chem. Biol. Drug Des. 2016, 88, 766–778. [CrossRef] 104. Huang, S.-M.; Hsu, P.-C.; Chen, M.-Y.; Li, W.-S.; More, S.V.; Lu, K.-T.; Wang, Y.-C. The Novel Indole Compound SK228 Induces Apoptosis and FAK/Paxillin Disruption in Tumor Cell Lines and Inhibits Growth of Tumor Graft in the Nude Mouse. Int. J. Cancer 2012, 131, 722–732. [CrossRef] 105. Li, W.-S.; Wang, C.-H.; Ko, S.; Chang, T.T.; Jen, Y.C.; Yao, C.-F.; More, S.V.; Jao, S.-C. Synthesis and Evaluation

of the Cytotoxicities of Tetraindoles: Observation That the 5-Hydroxy Tetraindole (SK228) Induces G 2 Arrest and Apoptosis in Human Breast Cancer Cells. J. Med. Chem. 2012, 55, 1583–1592. [CrossRef][PubMed] 106. Ahn, M.-Y.; Kim, T.-H.; Kwon, S.-M.; Yoon, H.-E.; Kim, H.-S.; Kim, J.-I.; Kim, Y.-C.; Kang, K.-W.; Ahn, S.-G.;

Yoon, J.-H. 5-Nitro-50-Hydroxy-Indirubin-30-Oxime (AGM130), an Indirubin-30-Oxime Derivative, Inhibits Tumor Growth by Inducing Apoptosis against Non-Small Cell Lung Cancer in Vitro and in Vivo. Eur. J. Pharm. Sci. 2015, 79, 122–131. [CrossRef][PubMed] 107. Liu, C.-Y.; Wu, P.-T.; Wang, J.-P.; Fan, P.-W.; Hsieh, C.-H.; Su, C.-L.; Chiu, C.-C.; Yao, C.-F.; Fang, K. An Indolylquinoline Derivative Promotes Apoptosis in Human Lung Cancer Cells by Impairing Mitochondrial Functions. Apoptosis 2015, 20, 1471–1482. [CrossRef][PubMed] 108. Manuel-Manresa, P.; Korrodi-Gregório, L.; Hernando, E.; Villanueva, A.; Martínez-García, D.; Rodilla, A.M.; Ramos, R.; Fardilha, M.; Moya, J.; Quesada, R.; et al. Novel Indole-Based Tambjamine-Analogues Induce Apoptotic Lung Cancer Cell Death through P38 Mitogen-Activated Protein Kinase Activation. Mol. Cancer Ther. 2017, 16, 1224–1235. [CrossRef] Molecules 2020, 25, 1615 25 of 25

109. Hernando, E.; Soto-Cerrato, V.; Cortés-Arroyo, S.; Pérez-Tomás, R.; Quesada, R. Transmembrane Anion Transport and Cytotoxicity of Synthetic Tambjamine Analogs. Org. Biomol. Chem. 2014, 12, 1771–1778. [CrossRef] 110. Yu, C.; Liu, Y.; Qin, Z. Metadherin Contributes to Epithelial-Mesenchymal Transition and Paclitaxel Resistance Induced by Acidic Extracellular PH in Nasopharyngeal Carcinoma. Oncol. Lett. 2018, 3, 3858–3863. [CrossRef] 111. Zou, Y.; Qin, X.; Xiong, H.; Zhu, F.; Chen, T.; Wu, H. Apoptosis of Human Non-Small-Cell Lung Cancer A549 Cells Triggered by Evodiamine through MTDH-Dependent Signaling Pathway. Tumor Biol. 2015, 36, 5187–5193. [CrossRef] 112. Kan, S.-F.; Yu, C.-H.; Pu, H.-F.; Hsu, J.-M.; Chen, M.-J.; Wang, P.S. Anti-Proliferative Effects of Evodiamine on Human Prostate Cancer Cell Lines DU145 and PC3. J. Cell. Biochem. 2007, 101, 44–56. [CrossRef] 113. Jiang, J.; Hu, C. Evodiamine: A Novel Anti-Cancer Alkaloid from Evodia Rutaecarpa. Molecules 2009, 14, 1852–1859. [CrossRef] 114. Wang, Z.-X.; Xiang, J.-C.; Wang, M.; Ma, J.-T.; Wu, Y.-D.; Wu, A.-X. One-Pot Total Synthesis of Evodiamine and Its Analogues through a Continuous Biscyclization Reaction. Org. Lett. 2018, 20, 6380–6383. [CrossRef] 115. Menna, M.; Fattorusso, E.; Imperatore, C. Alkaloids from Marine Ascidians. Molecules 2011, 16, 8694–8732. [CrossRef] 116. Keawprdub, N.; Houghton, P.; Eno-Amooquaye, E.; Burke, P. Activity of Extracts and Alkaloids of Thai Alstonia Species Against Human Lung Cancer Cell Lines. Planta Med. 1997, 63, 97–101. [CrossRef][PubMed] 117. Ji, X.; Xue, S.; Zhan, Y.; Shen, J.; Wu, L.; Jin, J.; Wang, Z.; Li, Z. Design, Synthesis and Antiproliferative Activity of a Novel Class of Indole-2-Carboxylate Derivatives. Eur. J. Med. Chem. 2014, 83, 409–418. [CrossRef] [PubMed] 118. Skouta, R.; Hayano, M.; Shimada, K.; Stockwell, B.R. Design and Synthesis of Pictet–Spengler Condensation Products That Exhibit Oncogenic-RAS Synthetic Lethality and Induce Non-Apoptotic Cell Death. Bioorg. Med. Chem. Lett. 2012, 22, 5707–5713. [CrossRef][PubMed]

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