European Journal of Medicinal Chemistry 46 (2011) 4769e4807

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European Journal of Medicinal Chemistry

journal homepage: http://www.elsevier.com/locate/ejmech

Mini-review Natural products: An evolving role in future drug discovery

Bhuwan B. Mishra, Vinod K. Tiwari*

Department of Chemistry, Centre of Advanced Study, Banaras Hindu University, Varanasi 221005, India article info abstract

Article history: The therapeutic areas of infectious diseases and oncology have benefited from abundant scaffold diversity Received 7 June 2011 in natural products, able to interact with many specific targets within the cell and indeed for many years Received in revised form have been source or inspiration for the majority of FDA approved drugs. The present review describes 29 July 2011 natural products (NPs), semi-synthetic NPs and NP-derived compounds that have undergone clinical Accepted 30 July 2011 evaluation or registration from 2005 to 2010 by disease area i.e. infectious (bacterial, fungal, parasitic and Available online 16 August 2011 viral), immunological, cardiovascular, neurological, inflammatory and related diseases and oncology. This manuscript is dedicated to Ó 2011 Elsevier Masson SAS. All rights reserved. Prof. Goverdhan Mehta, Indian Institute of Science, Bangalore.

Keywords: Natural products Clinical development Drug discovery Approved drugs

1. Introduction activities and are derived from natural sources, e.g., plants, animals and microorganisms, have been grouped as NPs. The compounds that Natural products have been the major sources of chemical diversity are derived from a NP template using semi-synthesis have been for starting materials while driving pharmaceutical discovery over the grouped in semi-synthetic NPs while the compounds that were past century. Historically pharmaceutical companies have utilized synthetically derived or in some cases inspired from a NP template plant extracts to produce relatively crude therapeutic formulations, have been classified as NP-derived compounds [3e5].Previous but with the advancement of antibiotics in the mid-twentieth century, reviews in this general area come from the 2005 reviews by Kingston drug formulations of fairly purified compounds have become more and Newman [6,7], Koehn and Carter [8], Paterson and Anderson [9]; typical [1]. The interesting chemicals identified as NPs are derived the 2006 reviews by Jones et al. [10], Gullo et al. [11],Wilsonand from the phenomenon of biodiversity inwhich the interactions among Danishefsky [12]; the 2007 reviews by Lam [13], Baker et al. [14], organisms and their environment formulate the diverse complex Harvey [15]; the 2008 review by Butler [16]. This review represents chemicalentities within the organisms thatenhance their survival and a thorough evaluation of publicly available data on NP-derived drugs competitiveness [2]. The therapeutic areas of infectious diseases and and templates. Compounds derived from primary metabolites (e.g. oncology have benefited from these numerous drug classes, able to steroids, nucleosides, prostaglandins, sialic acid and tyrosine), vita- interact with many specific targets within the cell, and indeed for mins (e.g. vitamin D and retinoids), hormones and protein fragments, many years have been central in the drug discovery and development. herbal mixtures, polyamines and porphyrin derivatives have not been Today, NPs are finding increasing use as probes to interrogate bio- listed exhaustively in this review. logical systems as part of chemical genomics and related researches. The review summarizes the 3 groups of compounds classified as 2. Drug approval processes NPs, semi-synthetic NPs and NP-derived compounds that have undergone clinical evaluation or registration form 2005 to June 2010 An Investigational New Drug (IND) application is submitted to by disease area i.e. infectious (bacterial, fungal, parasitic and viral), the FDA or EMA before commencement of clinical trials. Once immunological, cardiovascular, neurological, inflammatory and clinical trials are successfully completed, the applicant files a New related diseases and oncology. The compounds which have biological Drug Application (NDA) in the US or a Marketing Authorization Application (MAA) in Europe to seek approval for marketing the * Corresponding author. Fax: þ91 542 2368174. drug. The agency then responds in the form of an ‘approval letter’, E-mail addresses: [email protected], [email protected] (V.K. Tiwari). a ‘non-approval letter’ or an ‘approvable letter’.An“approval letter”

0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmech.2011.07.057 4770 B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807 allows the applicant to begin marketing the product, while a “non- reducing the need for the opioid medications. Otsuka Pharmaceutical approval letter” rejects the application. An ‘approvable letter’ in February 2007 signed an agreement with GW for further devel- Ò Ò informs the applicants that the agency have completed their opment and marketing of Sativex in the USA. Sativex efficiently scientific review and determined that the application can be reduces pain in patients with advance cancer [20] and has been rec- approved pending resolution of minor deficiencies identified in the ommended by the FDA for direct entry into Phase III trials. In letter or during an inspection of the manufacturing facilities. November 2009, GW Pharmaceuticals disclosed that recruitment for Ò a Phase II/III cancer pain trial of Sativex had been completed. In 3. Natural products based drugs approved during 2005e2010 March 2010, GW Pharmaceuticals provided an update on the progress Ò of regulatory submission for Sativex oromucosal spray for the A total of 19 NP based drugs were approved for marketing treatment of the symptoms of spasticity due to multiple sclerosis [21]. Ò worldwide in between the year 2005 to 2010 (Scheme 1), among Fumagillin (Flisint , Sanofi-Aventis, 3), an antimicrobial lead which 7 are classified as NPs, 10 as semi-synthetic NPs, and 2 as NP- capable of inhibiting the proliferation of endothelial cells, was derived drugs (Table 1). isolated from Aspergillus fumigatus [22]. In September 2005, France Ò VeregenÔ (Polyphenon E ointment), a defined mixture of approved 3 against intestinal microsporidiosis, a disease caused by catechins obtained from green tea, is the first ever herbal medicine the sporeforming unicellular parasite Enterocytozoon bieneusi, to receive FDA approval in 2006. VeregenÔ was developed by causing chronic diarrhea in immunocompromised patients [23]. MediGene AG and launched in the US by Bradley Pharmaceuticals There are presently nine b-lactams (two cephalosporins, six in December 2007 for topical use against genital warts. MediGene carbapenems and one penem) in clinical trials or undergoing drug signed an agreement with Solvay in 2009 for the licensing and registration. Among carbapenem-type b-lactams, doripenem 4 and supply of VeregenÔ in Germany, Austria, and Switzerland. In March thienamycin 5 are the ultra-broad spectrum injectable antibiotics. Ò Ò 2010, Solvay launched Veregen (10% ointment) in Germany [17]. Doripenem (Finibax , DoribaxÔ) 4, exhibiting a broad antibacterial Ò Sativex (GW Pharmaceuticals) is the world’s first pharmaceutical spectrum [24a] was launched in Japan by Shionogi & Co. in 2005. In Ò prescription medicine derived from the cannabis plant [18].Sativex , October 2007,Johnson & Johnson (J&J) obtained formal FDA approval a mixture of dronabinol 1 and cannabidol 2, was launched in Canada for use of 4 in intra-abdominal and urinary tract infections [24b]. Ò in April 2005 for neuropathic pain relief in multiple sclerosis [19],and Tigecycline (Tygacil , 6) is among a new generation of antibiotics it was also approved by Health Canada in August 2007 as an called glycylcyclines, and is structurally similar to tetracycline 7.It adjunctive analgesic for severe pain in advanced cancer patients, contains a centralized four-ring carbocyclic skeleton substituted at

Scheme 1. Drugs approved during 2005e2010. B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807 4771

Table 1 NP-derived drugs launched since 2005; lead compounds, classification and therapeutic area [17e117].

Year Generic name (trade name) Lead compound Classification Disease area Ò 2005 Dronabinol 1/Cannabidol 2 (Sativex ) Dronabinol 1/cannabidol 2 NPs Pain Ò 2005 Fumagillin 3 (Flisint ) Fumagillin 3 NPs Antiparasitic Ò 2005 Doripenem 4 (Finibax /DoribaxÔ) Thienamycin 5 NP-derived Antibacterial Ò 2005 Tigecycline 6 (Tygacil ) Tetracycline 7 Semi-synthetic NP Antibacterial Ò 2005 Ziconotide 8 (Prialt ) Ziconotide 8 NP Pain 2005 Zotarolimus 9 (EndeavorÔ stent) Sirolimus 10 Semi-synthetic NP Cardiovascular surgery 2006 Anidulafungin 11 (EraxisÔ/EcaltaÔ) Echinocandin B 12 Semi-synthetic NP Antifungal Ò 2006 Exenatide 13 (Byetta ) Exenatide-4 13 NP Diabetes 2007 Lisdexamfetamine 14 (VyvanseÔ) Amphetamine 15 NP-derived ADHD 2007 Retapamulin 16 (AltabaxÔ/AltargoÔ) Pleuromutilin 17 Semi-synthetic NP Antibacterial 2007 Temsirolimus 18 (ToriselÔ) Sirolimus 10 Semi-synthetic NP Oncology 2007 Trabectedin 19 (YondelisÔ) Trabectedin 19 NP Oncology 2007 Ixabepilone 20 (IxempraÔ) Epothilone B 21 Semi-synthetic NP Oncology Ò 2008 Methylnaltrexone 22 (Relistor ) Naltrexone 23 Semi-synthetic NP Pain Ò 2009 Everolimus 24 (Afinitor ) Sirolimus 10 Semi-synthetic NP Oncology 2009 Telavancin 25 (VibativÔ) Vancomycin 26 Semi-synthetic NP Antibacterial Ò 2009 Romidepsin 27 (Istodax ) Romidepsin 27 NP Oncology Ò 2009 Capsaicin 28 (Qutenza ) Capsaicin 28 NP Pain 2010 Monobactam aztreonam 29 (CaystonÔ) Aztreonam 29 Semi-synthetic NP Antibacterial

the D-9 position conferring broad spectrum activity. Tigecycline the oral secretions of the poisonous lizard Heloderma suspectum effectively binds to the 30S subunit of bacterial ribosome and blocks (Gila monster) [34,35]. Among the incretin (human hormone) the entry of amino-acyl tRNA molecules into the A site of the ribo- mimetics, 13 can mimic the antidiabetic or glucose-lowering some, thus inhibits protein translation [25]. Tigecycline was devel- properties of incretins. Eli Lilly obtained the FDA approval in April oped by Wyeth [26a] and in June 2005 the FDA approved it for 2005 while Amylin Pharmaceuticals gained the EMEA approval in treatment of complicated skin and skin structure infections November 2006 for the use of 13 as an adjunctive therapy in type 2 (cSSSIs) and intra-abdominal infections. Tigecycline was approved diabetes mellitus [36]. Amylin Pharmaceuticals, Eli Lilly and in Europe in May 2006, and a supplemental NDA for community- Alkermes in May 2009 submitted a NDA for subcutaneous dosing of acquired pneumonia (CAP) was submitted to the FDA in October 13 once weekly to the FDA, which was approved in July 2009. 2007 [26b]. Attention-Deficit Hyperactivity Disorder (ADHD), a neuro- Ò Ziconotide (Prialt , 8) is a synthetic form of the peptide u-con- developmental disorder in which dopaminergic and noradrenergic otoxin, which was isolated from the toxin of Conus magus,isanN-type neurotransmission are supposed to be dysregulated, is primarily voltage sensitive calcium channel blocker and is proposed to regulate characterized by the co-existence of attentional problems and neurotransmission by inhibiting pro-nociceptive neurochemical hyperactivity. Methylphenidate and amphetamines have been used releases in the brain and spinal cord, thus causing pain relief [27].In for ADHD management for many years but due to abuse potentials December 2004, the FDA approved 8 when given as an infusion using these drugs are controlled substances [37]. Lisdexamfetamine an intrathecal pump into the cerebrospinal fluid. In 2005, Elan (VyvanseÔ, NRP104) 14 consisting of dextroamphetamine coupled launched Ziconotide 8 in the US and Europe for the treatment of with the essential amino acid L-lysine was designed by New River patients suffering from chronic pain. Rights for marketing Ziconotide Pharmaceuticals to help ADHD. Intravenous administration 14 Ò (Prialt ) in Europe was obtained by Eisai in March 2006 [28]. produces effects similar to placebo and therefore is completely Zotarolimus 9, a derivative of sirolimus 10, is the active principle ineffective, however on oral administration it gets converted to of the EndeavorÔ stent that inhibits cell proliferation, preventing D-amphetamine 15 in the gastrointestinal (GI) tract [38].In scar tissue formation and minimizeing restenosis in angioplasty February 2007, New River Pharmaceuticals and Shire Pharmaceu- Ò patients [29]. Sirolimus 10 (Rapamune , Wyeth) was originally ticals obtained the FDA approval for use of 14 to help ADHD, and in discovered from the bacterium Steptomyces hygroscopicus as April 2007 Shire bought New River Pharmaceuticals. a promiscing antifungal agent [30] and is being used along with Pleuromutilin 16 is a metabolite of fungal origin that binds to the other coronary stents against restenosis of coronary arteries due to peptidyltransferase and exhibits antibacterial activity by inhibiting balloon angioplasty. In July 2005, Medtronic received European protein synthesis in bacteria [39]. Retapamulin (SB-275833) 17, approval for the sale of the EndeavorÔ drug-eluting coronary stent a semi-synthetic derivative of 16, is the first among pleuromutilin that consists of a cobalt-based alloy integrated with a biomimetic antibiotics developed by GlaxoSmithKline for topical use in impe- phosphorylcholine polymer [31]. In February 2008, Medtronic tigo caused by Gram-positive Staphylococcus aureus or Streptococcus Ò received FDA approval for the Endeavor in the treatment of coro- pyogenes [40]. GlaxoSmithKline gained FDA approval for 17 in April Ò nary artery disease [32a] while Cypher (sirolimus-eluting coronary 2007 [68] and the EMEA approval in June 2007 for a 1% retapamulin stent) is being marketed by Cordis (Johnson & Johnson) [32b]. ointment (called AltabaxÔ in the US and AltargoÔ in Europe). Ò Anidulafungin 11 (EraxisÔ in the US, EcaltaÔ in Europe), is a semi- Temsirolimus (Torisel , CCI-779, 18) is a sirolimus 10 derivative and synthetic derivative of the fungal metabolite echinocandin B 12. is an intravenous drug developed by Wyeth [41]. It was approved by Anidulafungin was originally developed for use against invasive and the FDA in late May 2007 and by the EMEA in November 2007 for use oesophageal candidiasis and candidemia by Eli Lilly and was licensed against renal cell carcinoma (RCC) [42]. Temsirolimus 18 is a semi- to Vicuron Pharmaceuticals, which was purchased by Pfizer in June synthetic derivative of sirolimus 10 and is the first mTOR inhibitor 2005. Pfizer gained the FDA approval in February 2006 (EraxisÔ in developed by Wyeth Pharmaceuticals [43]. Ò the US) and EMEA approval in July 2007 [33]. Trabectedin (Yondelis , ecteinascidin-743, ET-743, 19), a tetra- Ò Exenatide 13 (Byetta ), is a 39 amino acid peptide, structurally hydroisoquinoline alkaloid produced by Ecteinascidia turbinate [44] similar to glucagon-like peptide-1 (GLP-1) and was isolated from is sold by Zeltia and Johnson & Johnson for use in the treatment of 4772 B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807

CH CH3 3

OH OH

H2C H C 3 HO O CH3 CH3 CH3 H3C 1 2

O CH3 CH3 H HO CH H H 3 CH3 O H3C S OCH3 N H O N NH2 O S O HO N O H O O CO2H 4 3 HO CH H C CH H C CH H H 3 NH2 3 3 3 3 N N H H H C 3 OH S O N H O H3C N O N CONH2 HO H H3C HO 5 CH3 OH O OH O H3C CH3 N 6 HO CH 3 H OH

CONH OH 2 H2N-CKGKGAKCSRLMYDCCTGSCRSGKC-CONH2 OH O OH O 7 8

Ò advanced soft tissue sarcoma [45]. Trabectedin binds to the minor Methylnaltrexone (MOA-728, Relistor by Wyeth, 22), an N- groove of DNA and inhibits cell proliferation by disrupting the cell methyl derivative of naltrexone 23, contains a charged tetravalent cycle. It was approved by the EMEA in September 2007 for use nitrogen atom and is unable to cross the bloodebrain barrier, and against soft tissue sarcomas and ovarian cancer. In November 2009, so has antagonist effects throughout the body [49]. Methylnal- it received its second marketing authorization from the European trexone blocks peripheral opioid receptors activated by opioids Commission for the treatment of relapsed platinum-sensitive administered for pain relief and thus useful in management of Ò Ò ovarian cancer in combination with DOXIL /Caelyx . Presently, alcohol and opioid dependence [50]. In May 2007, Wyeth and trabectedin is in Phase II trials against pediatric sarcomas, breast Progenics filed a NDA for subcutaneous doses of 22 for the treat- and prostate cancers [46]. ment of opioid induced constipation and other pain indications. In Ixabepilone (IxempraÔ, BMS-247550, 20) is a semi-synthetic March 2008, Wyeth and Progenics reported that 22 failed in two derivative of epothilone B 21 produced by Sorangium cellulosum Phase III trials for intravenous use in treatment of post-operative [47]. Bristol-Myers Squibb (BMS) developed 20 as an anticancer ileus. In April 2008, Progenics and Wyeth announced that Health drug that binds directly to b-tubulin subunits on microtubules, Canada and the FDA have approved 22 for the treatment of opioid leading to the suppression of microtubule dynamics, blocking of induced constipation [51]. As of May 2009 an oral formulation of 22 cells in the mitotic phase, ultimately leading to cell death. In is under Phase II trials against opioid induced constipation in October 2007, the FDA approved ixabepilone 20 (IxempraÔ)as chronic pain. After acquisition of Wyeth by Pfizer in October 2009, Ò monotherapy and in combination with capecitabine (Xeloda ) the collaboration is continued by Progenics and Pfizer. against metastatic or locally advanced breast cancer patients Everolimus (LuveniqÔ or LX211, 24), a mTOR inhibiting deriv- resistant or refractory to anthracyclines, taxanes, and capecitabine ative of 10, is marketed as an immunosuppressant by Novartis Ò [48]. under the trade Afinitor for use in advanced renal carcinoma. In B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807 4773

March 2009 the FDA has approved 24 against advanced renal cell cutaneous in TCL patients that have received a minimum of one Ò Ò carcinoma after failure of Sutent (sunitinib) or Nexavar (sor- prior systemic therapy [57], while three Phase II trials for multiple afenib) [52]. myeloma and peripheral TCL are still recruiting patients. In January Telavancin (VibativÔ, TD-6424, 25), a semi-synthetic analog of 2010, Celgene completed the acquisition of Gloucester vancomycin 26, inhibits bacterial growth through binding to the D- Pharmaceuticals. Ala-D-Ala terminus of the bacterial peptidoglycan precursors [53]. Capsaicin 28, an active component of chili peppers belonging to Telavancin was discovered by Theravance, and is being developed the genus Capsicum,wasfirst isolated in pure and crystalline form in partnership with Astellas [54]. Theravance submitted a NDA in by John Clough Thresh in 1876 [58a]. Capsaicin 28 produces December 2006 and an MAA in May 2007 for use of 25 against a burning sensation when it comes in contact with tissues though Gram-positive cSSSIs, and MRSA, and this was approved in binding to the ion channel receptor vanilloid receptor subtype 1 September 2009 by the FDA. Theravance has also submitted 25 to (VR 1) [58b,c]. In November 2009, NeurogesX gained FDA approval Ò the FDA for a second indication for the treatment of nosocomial for Qutenza (a transdermal 8% patch of 28) against neuropathic pneumonia or hospital aquired pneumonia (HAP). In November pain combined with post-therapeutic neuralgia. In April 2010, Ò 2009, the FDA released a complete response letter to Theravance for NeurogesX launched Qutenza in US and is planning to market it in telavancin NDA against nosocomial pneumonia. Europe by Astellas Pharma Europe Ltd. [59]. Ò Romidepsin (depsipeptide, FK228, FR901228, Istodax , 27), Aztreonam lysine (CaystonÔ, 29), an inhaled lysine salt a naturally occurring histone deacetylase inhibitor obtained from formulation [60], wherein the b-lactam ring is alone and not fused the bacteria Chromobacterium violaceum [55], was developed and to another ring, has been evaluated by Gilead in various Phase III evaluated by Gloucester Pharmaceuticals in various Phase I/II trials trials against cystic fibrosis (CF) patients having a pulmonary sponsored by the National Cancer Institute (NCI) for use against infection of the Gram-negative bacteria Pseudomonas aeruginosa cutaneous and peripheral T-cell lymphoma (TCL) [56]. In November [61]. In February 2010, CaystonÔ was approved by FDA for use in CF Ò 2009, Istodax 27 was approved by the FDA against selective patients, however its safety and efficacy is yet to be established in 4774 B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807

13 HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS

NH2 H N NH2 NH2

CH3 O CH3

14 15 O CH2 OH

CH3 OH O CH3 OH CH3 O O CH3 R H O H C 3 CH H C 3 3 O OH O 16 R=OH O CH3 O 17 R= S CH CH O NCH3 3 3 O CH3 OCH3 CH3 O NO HO CH 3 CH3

H3C O O H O H3C HO CH3 O S N H3C CH3 N CH 18 3 O O

O O OH S CH3 O OH H3CO H3C N H3C NH CH3 H3C X CH HO 20 X=NH 3 21 19 X=O O OH O

pediatric patients or Burkholderia cepacia colonized patients [62]. led to unparalleled efforts by government, academia and the The drug is a proprietary formulation of aztreonam, an antibiotic pharmaceutical industry to discover other compounds from natural first launched in 1984 for intravenous use. sources for the treatment of bacterial infections, resulting in nearly all novel classes of antibiotics being from NP sourced scaffolds 4. Infectious diseases through 1962. Since the commercialization of penicillins in the 1940s, b-lactams that inhibit the formation of peptidoglycan cross 4.1. Antimicrobials links in the bacterial cell wall leading to bacterial death, have been the mainstay for treating community-acquired infections [65]. 4.1.1. Antibacterial agents Ceftobiprole medocaril (BAL-5788, 30) is a cephalosporin anti- NP-derived drugs have been crucial for anti-infective drug biotic with excellent activity against P. aeruginosa, MRSA and discovery, and the many of antibacterial drugs currently in clinical penicillin-resistant Streptococcus pneumoniae [66]. Ceftobiprole 30 use are NPs or were designed using NP templates. Several antibi- is given intravenously [67] and was filed for regulatory approval in otics have been discovered simply by measuring zones of inhibition the US and Europe in July 2007, after the successful completion of of bacterial strains on agar plates by applying whole broth or pivotal Phase III registration trials by Basilea Pharmaceutica and J&J extracts obtained from microbial ferments. Mining of the bacterial affiliated Cilag GmbH International for the treatment of cSSSIs. In genome is providing new avenues for recognition of crucial targets November 2008, the FDA declined to approve 30 and recom- for the discovery of antibacterial agents with reduced side mended completion of two new and well-controlled studies for effects [63]. Despite having complex structures the development of safety and efficacy accessment against cSSSIs. In addition, various a NP to an antibacterial drug mainly depends on its ability to Phase III trials are underway for HAP/CAP. Ceftaroline acetate (PPI- penetrate bacterial cell membranes [64]. The success of penicillin 0903, TAK-599, 31), originally discovered by Takeda is known to B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807 4775

HO

O CH3 H3C O OH O HO CH O 3 O O N CH CH O 22 HO H 3 3 O CH3 O HO CH3 NO CH3

O O O HO N O Br 23 HO H H3C CH3 CH3 O 24

OH NH H HO Cl N O O CH3 H R 1 H C N N O 3 H NH O O HN O S CH3 O HO O O HN S O O O O NH NH O HO O NH2 Cl O CH3 HN O H C CO H HO 3 2 CH O 27 3 H3C O N H NH N CH3 OH N HO COOH H2N OH O N O S O N O S H O OH R 2 29 OH O H N CH3 H3CO CH3 R = N 1 H 25 CH R = N PO3H2 3 2 H HO 28

26 R1 =H,R2 =H

exhibit efficient antibacterial activity against penicillin-resistant Faropenem daloxate (SUN-208, BAY-56-6824) 37 is a penem- S. pneumoniae. Cerexa licensed 31 from Takeda and the drug is type b-lactam licensed to Replidyne by Daiichi Suntory Pharma to currently in Phase II clinical trials by Forest Laboratories to use market it in conjunction with Forest Pharmaceuticals [74].In against cSSSIs and CAP [68]. December 2005, Replidyne submitted a NDA to the FDA for use of Tebipenem pivoxil (ME-1211, L-084, 32) is an advanced carba- 37 against acute bacterial sinusitis (ABS), acute exacerbation of penem being evaluated as a broad-spectrum antibiotic under Phase chronic bronchitis (AECB), CAP and uncomplicated skin and skin III trials in Japan by Meiji Seika for otolaryngological/respiratory structure infections (uSSSIs). In March 2007, the FDA agreed for infections [69]. Tomopenem (CS-023, RO4908463, R1558, Daiichi Phase III development of 37 with placebo-controlled trials, one Sankyo, 33) for use against common nosocomial infections [70], each in ABS and AECB along with two non-inferiority CAP trials. and PZ601 (SM-216601, Protez, licensed from Dainippon Sumi- These additional trials have delayed the launch of drug. Ò tomo, 34) for use against MRSA and Pseudomonas aeruginosaare, Dalbavancin (Zeven , BI-397, 38) is a second-generation lip- both are in Phase II trials [71]. ME1036 (CP5609) 35, a DHP-1-stable oglycopeptide antibiotic and semi-synthetic derivative of the tei- parenteral carbapenem in which a 7-acylated imidazo[5,1-b]thia- coplanin analog A40926 39. It was discovered by Biosearch Italia zole-2-yl group is substituted at carbapenem moiety, was licensed and is being developed by Pfizer to use against cSSSIs [75]. Vicuron by Cerexa and Forest Laboratories from Meiji Seika Kaisha. ME1036 Pharamaceutical (now part of Pfizer) in February 2005 filed a NDA has excellent in vitro activity against multidrug-resistant (MDR) to use 38 for the treatment of cSSSIs. In December 2007, the FDA Staphylococci and Enterococcus faecalis. ME1036 exhibits a broad released an approval letter to Pfizer for use of 38 against cSSSIs Gram-negative activity of the carbapenems (activity against ESBL- adult patients, including MRSA [76]. However, based on feedback producing Escherichia coli and Klebsiella pneumoniae), except for from regulatory authorities, Pfizer has withdrawn the marketing P. aeruginosa and is under Phase I evaluation [72].Pfizer is evalu- applications for running another Phase III trial for 38. ating sulopenem (CP-70429) 36, and a prodrug, PF-3709270, in Oritavancin (NuvocidÔ, LY-333328, 40), a chloroeremomycin 41 Phase I trial [73]. derivative obtained through semi-synthesis was discovered and 4776 B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807

OH N O CH H H 3 N N S N O H2N N O N O S O N O O O HO O 30 CH3 OH H H CH3 CH3 N H C O 3 S N N H H O OH N N S H N O O N HO P N O S N O N O S S H C N O O S 3 H3C CH 32 31 3 HO O OH OH H H CH3 H H CH3 H3C H3C S CH S O N 3 N H N N NH O 2 S O N N O NH O H HO NH H N O 34 O OH CH S 33 3 OH H H OH CH3 H H CH3 H H S H O H3C H3C H3C N N N S O N N O S N NH2 O O O O O O O HO O HO 35 O 36 37 O CH3

developed by Eli Lilly and acquired by InterMune in 2001 and linopristin (RPR202698, streptogramin B-type, 45) [83]. Streptog- transferred to Targanta Therapeutics in 2005. Oritavancin has the ramins inhibit bacterial protein synthesis through the synergistic ability to attach with two types of peptidoglycans and exerts binding of streptogramin A & B components to different sites on the antibacterial activity through inhibition of cell wall synthesis. Tar- peptidyltransferase domain of the 50S ribosomal subunit [84].In ganta submitted a NDA for approval of 40 to the FDA in February October 2008 Novexel announced for positive Phase II trials of NXL- 2008 [77], which was accepted for standard review with an 103 against CAP and cSSSIs, including MRSA [85]. established action date in December 2008. In December 2008, the MerLion Pharmaceuticals in July 2007 initiated Phase I trials of FDA stated that there was insufficient data to approve 40. Addi- friulimicin B 46, a lipopeptide antibiotic having activity against tionally, Targanta submitted a MAA for 40 to the EMEA that was Gram-positive bacteria through complex formation with accepted for review in June 2008. bactoprenol-phosphate, leading to the inhibition of peptidoglycan, The vancomycin-cephalosporin heterodimer TD-1792 42, and teichoic acid biosynthesis [86]. Friulimicin B is produced by combining the antibacterial activities of a glycopeptide and Actinoplanes friuliensis HAG 010964 and its structure was confirmed a b-lactam in one molecule, has been designed to target 2 key after the crystal structure of amphomycin tsushimycin (A-1437B, bacterial cell wall synthesis targets. TD-1792 42 is in clinical 47), an aspartic acid analog of 46 published in late 2005 [87]. development by Theravance, who has successfully conducted Phase Moli1901 (duramycin, 2262U90, 48), a polycyclic peptide II trials for safety and efficacy accessments against cSSSIs, including produced by Streptomyces cinnamoneum [88], is under clinical MRSA. In July 2007, Theravance disclosed that 42 met primary and development by AOP Orphan in collaboration with Lantibio in secondary endpoints in a non-inferiority trial compared to vanco- Europe. Moli1901 enhances chloride transport and increases fluid mycin 26 [78]. secretion in vitro, thus has clinical indication against CF [89]. After Ramoplanin factor A2 (ramoplanin, 43), is the major component successful Phase I trials [90], aerosolized 48 was evaluated under of the lipopeptide antibiotic drugs derived from strain ATCC 33076 Phase II clinical development in Europe with positive results of Actinoplanes [79] which exerts antibacterial activity by inhibiting announced in adolescents and adults with CF in March 2007. Lan- bacterial cell wall synthesis. Ramoplanin factor A2 43 can form U- tibio is also investigating an ophthalmic solution of 48 in Phase II shaped structures with the ability to bind and capture Lipid II (C35- clinical trials for the treatment of dry eye syndrome. Omiganan 49, MurNAc-peptide-GlcNAc), a specific intermediate in membrane an analog of antibacterial peptide indolicidin 50 which was origi- formation [80]. Oscient Pharmaceuticals licensed the North Amer- nally purified from neutrophils of bovines [91], has significant ican rights for orally active ramoplanin 43 from Vicuron and eval- activity against infections caused by antibiotic-resistant and uated it in Phase II trials for GI tract infections caused by Clostridium sensitive bacteria. Indolicidin consists of 13 amino acids and has the difficile [81,82]. highest tryptophan content among the known proteins with ami- The NXL-103 (XRP2868), discovered by Sanofi-Aventis, is an dation at the carboxyl terminus [92]. Like other cationic peptides, orally available mixture (70:30) of two semi-synthetic streptogra- omiganan exerts antibacterial activity through interaction with the mins, flopristin (RPR132552A, streptogramin A-type, 44) and bacterial cytoplasmic membrane, and was developed by MIGENIX B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807 4777

and licensed to Cadence Pharmaceuticals for catheter-related accepted by FDA in December 2008 [96]. In placebo-controlled infections (coded OmigardÔ, CPI-226, MBI-226), and Cutanea Life non-human primate studies by Advance Life Sciences, RestanzaÔ Sciences for dermatological diseases (coded as CLS001, MX-594AN). has demonstrated a clinically and statistically significant survival A Primary end point was not achieved in a Phase III trial by Cadence rate in anthrax, plague and tularemia. In September 2009, orphan Pharmaceuticals, and additional Phase III trials using a gel-based drug designation was granted to 52 by the FDA for use in plague and formulation are underway. Cutanea Life Sciences have success- tularemia. A bridged bicyclic derivative, EP-420 (EP-013420, 53)is fully evaluated 49 in Phase II trials (2007) while the Phase III trials under Phase II clinical trials by both Enanta and Shionogi for for treatment of rosacea, a chronic inflammatory skin disorder, are treatment of CAP [97]. BAL19403 is a macrolide antibiotic whose underway. antibacterial spectrum covers clinical isolates of Propionibacterium Among the group of macrolide antibiotics, erythromycin 51, acnes with mutations in the 2057 to 2059 region of 23S rRNA obtained from actinomycetes, has ability to bind with the pepti- conferring resistance to erythromycin and clindamycin [98]. Basilea dyltransferase site of 50S ribosomal subunit, and can exert anti- has reported the first clinical data for 54 in the treatment of acne bacterial activity by the inhibition of protein synthesis [93]. [99]. Ò Cethromycin (ABT-773, RestanzaÔ, 52), EP-420 53 (by Enanta The first approved ketolide, telithromycin (Ketek , 55)was Pharmaceuticals), and BAL-19403 54 (by Basilea), are three semi- evaluated in Phase II/III clinical trials by French pharmaceutical synthetic ketolide derivatives of 51 that are in clinical development. company Hoechst Marion Roussel (later Sanofi-Aventis) in 1998. Cethromycin was developed originally by Abbott Laboratories [94], Latter on, telithromycin was approved by the European Commis- and later acquired by Advanced Life Sciences to use against CAP sion in July 2001 and subsequently went on sale in October 2001. In [95], and post-exposure to anthrax inhalation. A NDA by Advanced the US, 55 had received the FDA approval in April 2004 against the Life Sciences for the use of 52 against mild-to-moderate CAP was respiratory infections. Telithromycin displays bactericidal activity 4778 B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807

OH NH2 H C O 3 OH CH3 O OH O O Cl OH O O

HO OH Cl O O O H H H O N N N N N N CH3 H H H HN O O CH3 O O CH3 NH2 NH OH OH HO O 42 N H H N N S

H2N O N N S Cl O

CO2H

by blocking the progression of the growing polypeptide chain trial by Cumbre for the treatment of infections caused by gram- through binding with the 50S subunit of ribosome [100]. positive cocci [106]. Tiacumicin B (OPT-80, PAR-101, 56), an actinomycete-derived macrolactone, isolated by Abbott [101a], is in Phase III trials 4.1.2. Antifungal agents against C. difficile-associated diarrhea (CDAD) by Optimer Phar- Fungal infections of the bloodstream and organs, e.g., perito- maceuticals [101b]. Tiacumicin B exerts antibacterial activity by nitis, meningitis and pneumonia, are among the important causes inhibition of RNA synthesis in bacteria [101c]. The PTK-0796 (MK- of morbidity and mortality in organ transplant recipients [107]. 2764, 57), an aminomethylcycline with excellent activity against Despite major advances in drug chemotherapy, fungal infections both Gram-positive and Gram-negative strains, was discovered and are still a challenge, particularly in the growing number of immu- evaluated by Paratek in various Phase II trials against common nosuppressed patients seen in modern medical facilities. Despite hospital infections. The PTK-0796 is a bacterial protein synthesis having a cell wall, fungi are more similar to mammalian cells than inhibitor that was in-licensed by Novartis form Paratek for collab- to bacteria at the cellular level; therefore treatment of mycotic orative Phase III clinical development. In October 2009, Novartis infections is very difficult [108]. gained exclusive rights for marketing 57 as oral broad-spectrum Fewer antifungal candidates are undergoing clinical evaluation antibiotic against MRSA, MDR S. pneumoniae and vancomycin- in which only 2 are NP-derived (aminocandin, 61 and SPK-843, 62). resistant enterococci [102]. Echinocandins that inhibit the synthesis of glucan in cell wall are Eisai has designed the second-generation lipid A antagonist known to exert limited toxicity in human due to lack of biological eritoran (E5564, 58) [103a] from Rs-DPLA 59, a non-toxic lipid target, 1,3-b-D-glucan synthesis, and thus, are significant against A analog originally isolated from Rhodopseudomonas sphaeroides invasive infections by Candida species [109]. Among semi-synthetic Ò [103b]. Eritoran inhibits the endotoxin response through antago- echinocandins, caspofungin (first launch 2001, Cancidas , Merck), Ò Ò nism of the Toll-like receptor 4 (TLR4) [104a], and is currently in micafungin (first launch 2002, Mycamine /Funguard , Astellas) Phase III development by Eisai against sepsis caused by Gram- and and anidulafungin 11 (first launch 2006, EraxisÔ/EcaltaÔ, negative bacteria [104b]. Pfizer) have been approved since 2001. CBR-2092 60, a hybrid antibiotic combining rifamycin SV and Deoxymulundocandin 63, originally isolated from the fungus 4H-4-oxo-quinolizine, is being developed by Cumbre Pharmaceu- Aspergillus sydowii [110], is the lead compound of aminocandin ticals. The studies with S. aureus have shown that CBR-2092 brings (NXL-201, IP960, HMR-3270, 61), an investigational drug with rifampin-like effects to RNA synthesis and quinolone-like effects to excellent activity against Candida albicans and C. tropicalis [111].In DNA synthesis in rifampin-susceptible and resistant strains, December 2006, Novexel and Indevus signed an agreement over respectively [105]. CBR-2092 is supposed to exert antimicrobial the out-licensing of 61. The Dutch company APARTS BV has activity through combined effects on RNA polymerase, DNA top- successfully completed Phase I trials for SPK-843 62, obtained oisomerase IV, and DNA gyrase. Currently, CBR-2092 is in Phase IIa through semi-synthesis of patrician-A 64 produced by Streptomyces B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807 4779

aureofaciens. SPK-843 can destabilize the cell membrane of fungi In the 1970s, artemisinin 65, an important antimalarial drug was like other polyenes [112]. Kaken Pharmaceuticals has restarted identified from traditional Chinese medicine Artemisia annua. Phase II trials of 62 for treatment of systemic mycosis. APARTS BV Arterolane (RBx11160, OZ-277, 66), a synthetic trioxolane modeled has acquired world wide rights for the development of 62 and on artemisinin 65 pharmacophore, is being evaluated in combina- a license for Japan has been signed while contracts are still pending tion with piperaquine (a synthetic bisquinoline antimalarial drug) with US and European companies [113]. to fight against malaria by Ranbaxy [116]. In May 2009, Ranbaxy announced for commencement of Phase III clinical trials of 66 in 4.1.3. Antiparasitic agents combination with piperaquine phosphate in India, Bangladesh and Despite the fact that several NPs have been tested against Thailand to treat Plasmodium falciparum malaria [117]. protozoans followed by the implementation of heroic vector- Paromomycin 67 (HumatinÔ, King Pharmaceuticals), an ami- control measures, the incidence of parasitic infections has noglycoside antibiotic first isolated from Streptomyces krestomuce- increased globally [114]. The use of medicinal plants against para- ticus [118a], was developed as therapeutic agent against visceral sitic diseases has been traced from ancient records i.e. Cinchona leishmaniasis by the Institute for OneWorld Health [118b]. Paro- calisaya (bark), Strychnos pseudoquina (bark), Deianira erubescens momycin has orphan drug status and was approved by the Drug- (roots and leaves) and Remijia ferruginea (bark) [115]. Controller General of India in September 2006 against visceral 4780 B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807

NH H-Ala-Lys-Gln-Ala-Ala-Ala-Phe-Gly-Pro-Phe-Abu-Phe-Val-Ala-HOAsp-Gly-Asn-Abu-LysOH S S S 48

ILRWPWWPWRRK-NH2 ILPWKWPWWPWRR-NH2 N O 49 50 H3C CH3 O H C OH 3 H C 3 H C CH OH 3 3 HO CH N CH3 H 3 O N H3C H3C HO O H C O O CH 3 O 3 O N CH3 CH3 CH3 H3C H3C HO O O OCH3 O O CH O 3 CH3 CH3 OH O O O CH3 51 CH3 52 N N N N O N N

O N CH3 H3C O S CH3 H3C CH3 O OCH3 O N O H C HO H C H 3 3 O N CH3 CH3 CH3 N CH3 H3C H C HO H3C CH3 3 O O O CH H3C H3C HO 3 O O CH O 3 O O OCH3

O O CH3 CH3 O OH CH 3 CH3 53 54

leishmaniasis (VL) [119]. Paromomycin 67 is an off-patent antibiotic 2009, Myriad Genetics announced for the acquisition of all rights marketed in the US to treat intestinal parasites. In February 2008, from Panacos for 69 [122]. King Pharmaceuticals discontinued the sale of HumatinÔ but the Ribavarin 70 is a NP-derived compound having structure based substance is continually available in the US from another upon the Streptomyces-derived nucleoside antibiotics pyrazomycin manufacturer. and showdomycin, isolated in the 1960s, was marketed as ‘Rebetol’ in the US by Schering Plough with Valeant Pharmaceuticals until Ò 4.1.4. Antiviral agents 2005. Taribavirin (Viramidine , ribamidine, 71), a liver-targeting The single celled viruses represent the smallest existing life- prodrug of ribavirin 70 [123], is under Phase II/III development by form causing most common (i.e. cold, influenza, chickenpox and Valeant Pharmaceuticals against chronic hepatitis C virus (HCV) in cold sores) to greatest human health risk (i.e. ebola, AIDS, avian treatment-naive patients. Taribavirin is the standard treatment influenza and SARS). Significant research and development over the with interferon a-2b for HCV, and gets converted inside the liver by last 25 years into antiviral drug discovery has resulted in the adenosine deaminase to 70. In 2006, Valeant had announced the identification of important antiviral drugs like betulinic acid 68, results of Phase III trials, in which 71 failed to meet the non- a triterpenoid obtained from bark of Betula pubescens [120a]. inferiority efficacy endpoints. In 2007, Valeant initiated a Phase Betulinic acid was originally identified as a weak inhibitor of HIV IIb trial for 71 at higher doses, and reported the final results in June replication by Lee and co-workers at the University of North Car- 2009 against HCV [123]. olina [120b]. Betulinic acid can inhibit topoisomerase I [121a], and MBI-3253 (celgosivir, 6-O-butanoylcastanospermine, 72), a semi- is being evaluated in Phase I trials as a cancer chemo-preventive synthetic analog of castanospermine 73,wasfirst isolated from the agent. Bevirimat (PA-457, 69), extracted from a Chinese herb seeds of Castanospermum australe [124a]. Castanospermine is an Syzygium claviflorum is under Phase IIb trial in combination therapy inhibitor of some glucosidase enzymes, and has excellent antiviral by Panacos [121b]. Bevirimat is believed to inhibit HIV through activity [258]. In January 2009, MIGENIX disclosed the completion of maturation inhibition and blocks HIV maturation by inhibiting the Phase II clinical studies [124b] of 72 as a ‘triple combination’ (with final step of the HIV Gag protein processing. In December 2007, peginterferon a-2b and ribavirin 70)anda‘double combination’ (with Panacos announced the results of Phase IIb trial while in January peginterferon a-2b) in HCV patients. An exclusive option agreement B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807 4781

H3C OH H3C OH HO O CH H 3 O O OCH3 H C H C CH3 3 3 H C O O OH O 3 O OH O H3C Cl O H3C OH H C N H3C 3 OH N 56 Cl N O H3C H3C CH3 H3C CH3 CH3 N N N H H O OCH3 OH H C CH O H 3 3 H CH CH N CH3 H3C H C 3 3 N 3 H3C HO H3C CONH2 O O O CH OH 3 OH O OH O O O 55 57 CH3

OCH3 OH O O O O H O PO O H O PO O 2 3 O HO 2 3 O HO O O HN O O HN O OPO H O HN 3 2 HN OPO3H2 H3CO HO HO O O O O O O

CH 3 CH3 CH3 CH3 H3C

H3C H3C 58 59 CH3 CH3

H3C O CH3 CH3 CH3 O

H3CO OH OH CH3 O OH OH CH3

H3C NH O

N F CO2H O N N O OH O N N CH3 60 CH3 CH3

with United Therapeutics Corporation (UTC) was signed by MIGENIX NIM 811, cyclosporin 29, MeIle4-cyclosporin, 75), a NP discovered by for further development of 72 which was discontinued in April 2009. Sandoz (now Novartis) with comparatively less immunosuppressive MIGENIX are currently seeking other strategic options for their drug activity (1700 times less than cyclosporin 74) with favorable safty development programe [125]. profile [127], is in Phase I trials for anti-HIV and HCV activity. Debio- Cyclosporin 74, a fungal cyclic peptide consisting of 11amino acids 025 (UNIL025, MeAla3EtVal4-cyclosporin, 76) is a cyclophilin inhib- obtained from Beauveria nivea, is an immunosuppressant that exerts itor that displays 7000 times less immunosuppressive activity than antiviral activity through inhibition of cyclophilin. However, devel- 74, and is in various Phase IIb trials by Debiopharm for the treatment opment of 74 as antiviral drug is not possible due to calcineurin- of HCV [128]. Debio-025 acts with a novel mechanism of action by related and immunosuppressive side effects [126]. NIM 811 (SDZ binding to cyclophilin A (CypA) [129a]. In February 2010, Novartis in- 4782 B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807

licensed the exclusive rights to develop and market 76,aspotential causing sever damage to membrane while remains inactive against first-in-class antiviral agent except in Japan [129b]. Gram-negative bacteria, yeasts and fungi. The aRigen Pharmaceu- 4-Methylumbelliferone 77, an active ingredient of nutraceutical ticals are developing injectible, gel, and cream of 79 in various Ò product Heparvit by MTmedical Institute of Health and BioMonde, Phase I/II trials against MRSA and acne. In August 2009, New Energy is currently in Phase II development against HBV and HCV [130a]. and Industrial Technology Development Organization (NEDO) in The chinese academy of military medical sciences have started the Japan had selected the aRigen Pharmaceuticals for funding two- clinical evaluation of HIV-1 integrase inhibitor [130b], 1,5-DCQA thirds of the R&D costs for the development of 79 as first-line (1,5-di-O-caffeoylquinic acid, 78), extracted from Inula Britannic, anti-MRSA product candidate under the Innovation Promotion for the treatment of HIV. In 2006, Chinese scientists have initiated Program (IPP) until February 2011 [133]. the human trials of 78 to treat HIV/AIDS and hepatitis B [131]. WAP-8294A2 (JA-002, 79), a major component of the antibac- 4.2. Halted or discontinued compounds in infectious diseases terial complex produced by Gram-negative Lysobacter species, is potentially effective against the treatment of MRSA, cSSSIs, pneu- Rifalazil (ABI-1648, KRM-1648, 80) is a new generation semi- monia and septicemia [132]. WAP-8294A2 exerts antibacterial synthetic rifamycin B 81 derivative, that was evaluated by Activ- activity by selective interaction to membrane phospholipids, Biotics, and failed in a Phase III trial for the treatment of the B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807 4783

intermittent claudication, associated with peripheral arterial The two orally bio-available pleuromutilin derivatives, 565154 disease [134]. In December 2007, ActivBiotics went on sale for all and 742510, being evaluated in Phase I trial, were dropped by GSK the proprietary assets that opened a new hope for 80 to re-enter in September 2007 pipeline products. Artemisone (BAY 44-9585) clinical evaluation with a different company. 83, a semi-synthetic derivative of artemisinin 63 having low lip- Incyclinide (Col-3, 82), is a chemically modified tetracycline ophilicity and negligible neuro- and cytotoxicity in vitro and in vivo, which was evaluated by NCI and CollaGenex for the treatment of was first synthesized at Hong Kong University [136]. BAY 44-9585 various cancers (including a Phase II trial against Kaposi’s sarcoma), 83 exhibits efficient activity against malarial parasite compared to and rosacea. In July 2007, CollaGenex discontinued their acne current artemisinin. Bayer was evaluating 83 as a potential anti- programme with 82 due to disappointing results in Phase II trial malarial [137] in various Phase II trials but in last few years, there is [135]. no information available about the further development of 83. 4784 B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807

Calanolide A 84, a coumarin inhibiting non-nucleoside reverse treatment of neuropathic pain in cancer patients [143b]. Shanghai transcriptase [138] was first obtained from Calophyllum lanigerum Institute of Material Medica has synthesized Debio 9902 (ZT-1, 90) trees in Malaysia with potent activity against HIV-1 [139],was [144], a prodrug of 87, and licensed it to Debiopharm. In June 2007, licensed and evaluated to Phase II clinical trials by Sarawak Medi- Debiopharm announced the positive results of a Phase IIa trial for chem Pharmaceuticals. After purchase of the remaining 50% of safty and ef ficacy of 90 in treatment of mild Alzheimer’s disease. An Sarawak Medichem and full rights from Advanced Life Sciences by Independent Data Safety Monitoring Board (IDSMB) in March 2008, Sarawak Government in late 2006, no subsequent announcement recommended Debiopharm to continue Phase II study of 90 without for further drug development has been made. modification in Alzheimer’s patients. In October 2008, Debiopharm announced for starting of tablet formulation bridging study under 5. Neurological diseases IND for Alzheimer’s patients [145]. Lobeline 91, a piperidine alkaloid found in Lobelia species (such Neurological diseases involve the disease of central, peripheral, as Lobelia inflata, Lobelia tupa, Lobelia cardinalis, Lobelia siphilitica) and autonomic nervous systems. Historically, the plant alkaloids and Hippobroma longiflora, has been used traditionally as an emetic, such as morphine 85 (from Papaver somniferum), cocaine (from respiratory stimulant and more recently as a tobacco smoking Erythroxylon coca) and physostigmine 86 (from Physostigma ven- cessation agent [146]. Lobeline acts as a VMAT2 ligand [147a,b] that enosum) have been used to treat sever pain and central nervous reduces the methamphetamine induced dopamine release. Yaupon system (CNS) diseases. A sesquiterpene alkaloid, huperzine-A 87,an Therapeutics and NIH are evaluating 91 in Phase II trials as acetylcholinesterase (AChE) inhibitor [140a] isolated from firmoss a dopamine modulating agent for the treatment of methamphet- Huperzia serrata [140b], is under clinical development by Chinese amine addiction and ADHD [147c]. scientists for treatment Alzheimer’s disease. NIA, a division NIH is Anabaseine 92, a neurotoxic principle identified from marine evaluating 87 when administered orally in Phase II trials against worms of the phylum Rhynchocoela [148a], stimulates a wide Alzheimer’s disease [141]. Morphine-6-glucuronide (M6G) 88, variety of nicotinic acetylcholine receptors (AChRs), especially the a glucuronide derivative produced by metabolism of 85 in human neuromuscular [e.g. a12b1gd (embryogenic) or a12b1g 3 (adult)] body, was evaluated as analgesic by CeNeS Pharmaceuticals under and a7 AChRs [148b]. The 3-(2,4-Dimethoxybenzylidene)-anaba- Phase II and III trials in Europe [142a]. In 2007, a successful Phase III seine (DMXBA also called GTS-21, 93), a synthetic derivative of 92, study demonstrated that 88 effectively reduces pain equivalent to 85 was evaluated by Kem’s University of Florida in a sponsored with significant reduction in vomiting, post-operative nausea, research by Taiho Pharmaceutical against Alzheimer’s disease sedation and other common side effects. In June 2008, a bio- [149]. In April 2006, CoMentis (previously Athenagen) disclosed for pharmaceutical company PAION acquired the CeNeS Pharmaceuti- acquiring the assets of Osprey Pharmaceuticals, who had licensed cals and announced for completion of two Phase III trials by GTS-21 93 from the University of Florida. CoMentis have completed November 2008 [142b]. KRN-5500 89, a spicamycin derivative a Phase II trial in Alzheimer’s disease and are assessing 93 in various produced by Streptomyces alanosinicus [143a], was evaluated for Phase I and II trials for assessment of safety and cognitive safety and efficacy in Phase I trial by DARA BioSciences against improvement in ADHD patients. neuropathic pain. Currently, DARA BioSciences are conducting Phase Tetrodotoxin (TectinÔ, Wex Pharmaceuticals) 94, a potent IIa trials of 89 as an intravenously (IV) administred medicine for the neurotoxin extracted and purified from the puffer fish [150a] by

H3C O CH3 CH3 CH3 H3C O CH3 CH3 CH3 O O

H3CO OH OH CH3 H3CO OH OH CH3 O OH O CH3 O OH OH CH3 H3C NH H3C NH

O O O O N O O O CO2H O CH3 CH N 3 HO CH3 N 80 CH3 81

CH H3C 3 H H CH3 OH O CH3 H3C H O H N S

CONH2 O O O OH O OH O OH O O O O O

H C OH CH3 3 82 83 CH3 84 B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807 4785 means of a proprietary process developed by Wex Pharmaceuti- the Phase IIa trial demonstrating oral doses 1.25 or 2.5 g of SRT501 cals, is able to block the action potentials in nerves through are safe and tolerable when administered twice daily for 28 days in binding to sodium channels in cell membrane [150b].Wexin type 2 diabetes. Similar Phase IIa cancer trial with SRT501 is colaboratin with Chinese medical institute, are evaluating 94 for underway [164]. the treatment of cancer pain [151a] and management of opiate Cannabinoids, a unique group of secondary metabolites found in withdrawal symptoms in Phase III and I trials, respectively. Wex the cannabis plant (Cannabis sativa)andothers,areresponsiblefor Pharmaceuticals are also conducting Phase IIa clinical study for 94 the plant’s peculiar pharmacological effects [165].CP7075(IP751, against neuropathic pain caused by chemotherapy in patients with ajulemic acid, CT-3, 99) is a synthetic cannabinoid that suppress cancer [151b]. inflammatory cytokines, including IL-1b and matrix metal- Conotoxins, a group of neurotoxic peptides obtained from cone loproteinases (MMPs) through a peroxisome proliferator-activated snail of genus Conus, are supposed to modulate the activity of ion receptor (PPAR) g-mediated mechanism [166]. Pre-clinical toxi- channels [152]. Xen-2174 95, a 13 amino acid peptide with 2 cology and pharmacology studies of 99 was evaluated by Indevus cysteine bridges that targets the norepinephrine transporter (NET) Pharmaceuticals and later in October 2007, the drug was licensed to [153], was originally discovered by researchers at the University of Cervelo Pharmaceuticals for further manufacturing and pre-clinical Queensland who characterized the various effects of Conus mar- studies in preparation for Phase I trials in neuropathic pain [167]. moreus venom. Xenome are evaluating 95 in Phase II trials against acute post-operative pain and chronic pain in cancer patients who 5.1. Halted or discontinued compounds in neurological diseases are no longer responsive, minimally responsive, or intolerant to morphine and hydromorphone [154]. One of the major cap- CEP-1347 (KT-8138) 100 is a semi-synthetic derivative of K-252a saicinods, capsaicin 28, has been found significant in clinical 101 [168a], a CaM kinase and phosphorylase kinase inhibiting conditions like osteoarthritis [155a], post-herpetic neuralgias, alkaloid isolated from Nocardiopisis species [168b,169], was evalu- psoriasis [155b] and diabetic neuropathy [155c]. As discussed ated by Cephalon and H Lundbeck AS against Parkinson’s disease. Ò earlier that Qutenza (an 8% trans-dermal patch of capsaicin 28) CEP-1347 100 was discontinued by May 2005 due to lack of efficacy has been approved in 2009, Anesiva are evaluating different in various Phase II/III trials [169]. formulations of capsaicin 28 (coded 4975, ALGRX 4975) for treat- Devacade 102 is an orally active cholecystokinin A (CCK A) ment of severe post-surgical pain, post-traumatic neuropathic pain antagonist whose structure was based upon asperlicin 103 [170], and musculoskeletal diseases in various clinical trials. In December a mycotoxin derived from Aspergillus alliaceus. ML Laboratories, 2008, Anesiva announced to attain primary end point while eval- who evaluated 102 in Phase II trials for the enhancement of opioid uating AdleaÔ (ALGRX 4975) in a Phase III clinical trial against pain relief, has discontined the clinical development in May 2005. acute pain following orthopedic surgery [156a]. Winston Labora- Cognetix were associated with clinical developments of con- tories undertook Phase III trials of civamide (cis-capsaicin, zucap- otoxins isolated from marine cone snail. Contulakin G (CGX-1160) saicin, WL-1001) for the treatment of episodic cluster headache and 104 is an orphan drug designated lead of Cognetix that has completed knee osteoarthritis. In October 2008, a NDS by Winston was filed in a Phase Ib clinical trial against chronic and intractable pain. The Ò Canada for Civanex (civamide 0.075%) for releving osteoarthritis further clinical evaluations of CGX 1160 104 and conantokin-G (CGX- Ò pain. In February 2009, an orphan drug designation to Civanex 1007) 105 are on hold until more funding can be obtained. was given by FDA with NON release to Winston Pharmaceuticals in ACV1 (Vcl.1, 106), a neuronal nicotinic receptor antagonist that October 2009 [156b]. displays selectivity for the a9a10 subtype, was identified by Phlorizin 96, a polyphenolic glucoside obtained from apple tree, screening some uncharacterized conopeptide sequences from the lowers glucose plasma levels and improves insulin resistance by venom duct of C. victoriae using PCR [171a]. ACV1106 was evaluated inhibiting sodium glucose co-transporters (SGLTs) [157]. Poor by Metabolic Pharmaceuticals against neuropathic pain in diabetes intestinal absorption and inactivation by lactase-phlorizin hydro- and post-herpetic neuralgia. In August 2007, Metabolic announced lase were serious drawbacks that restricted the development of 96 for discontinuation of Phase IIa trials of 106 due to less activity as drug [158]. Dapagliflozin (BMS-512148) 97, an analog of 96 and against the human a9a10 nAChR receptor compared to equivalent selective inhibitor of SGLT2 is being evaluated by by Bristol-Myers rat receptors [171b]. Squibb in partnership with AstraZeneca as a potential treatment Torrey-Pines Therapeutics (formally Axonyx) evaluated phen- for type 2 diabetes [159]. In October 2009, the BMS announced the serine 107, an AChE inhibitor showing disease modifying action by results of Phase III trial of 97, a 24-week study showing statistically reducing plaque through inhibition of APP synthesis as well as greater mean reductions of body weight compared to individuals provides symptomatic relief [172]. In November 2008, QR Pharma Ò receiving placebo [160]. Among other phlorizin-inspired deriva- licensed 107 from TorreyPines, and evaluated Posiphen (a (þ)- tives in development, the Phase II trials for GSK-189075 in enantiomer of 107) against Alzheimer’s disease. In May 2009, QR treatment-naive type 2 diabetes mellitus have been completed by Pharma reported the failour of 107 in placebo-controlled Phase III GlaxoSmithKline in June 2008. trials. In April 2009, QR Pharma received investment from Ben Resveratrol 98, a triphenolic stilbene isolated from a variety of Franklin Technology Partners for further clinical development of plants has been reported significant in the treatment of cancer, 107. In February 2010, QR Pharma gained US Patent for the use of Ò ischemic injuries and cardiovascular disease [161]. In 2003, Howitz Posiphen against cognitive impairments combined with Down and co-workers reported that resveratrol 98 is an agonist of syndrome [173]. Saccharomyces cerevisiae silent information regulator (Sir2) protein, Gantacurium chloride (AV430A, GW280430A, 108), an a class III histone deactylase whose presence results in extended ultrashort-acting, non-depolarizing surgical neuromuscular blocker lifespan of S. cerevisiae, Caenorhabditis elegans and Drosophila (NMB), was evaluated by GSK in Phase I trials demonstrating melanogaster [162]. In 2006, Italian scientists announced the posi- excellent safety and potent neuromuscular blocking effects [174]. tive result of 98 supplementation in Nothobranchius furzeri,afish Avera in 2002 gained acquisition assets from GSK and completed that demonstrated an increased median life span by 56% [163]. Phase I and II developments of 108. Currently, Avera are seeking to Sirtris proprietary formulation of 98, SRT-501, targets SIRT1 and out-license the development and commercialization rights for 108. acts by increasing mitochondrial activity, hence is significant Some phlorizin-inspired derivatives discontinued from devel- against diabetes and obesity. Sirtris have successfully completed opment are KGT-1681 (GSK and Kissei), TS-033 (Taisho) and YM- 4786 B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807

HO H3C H

H H3C N O N O O H3C N CH3 N O CH3 H C H H N H 3 H2N RO HO2C CH3 HO O 86 87 85 R = H; 88 R= HO OH HO OH NN O H N O N NH H3C N H H N CH HO 3 89 O OH OCH3 O OH H

H3C N O OCH3 N CH3 91 HO N

H CO Cl N N 3 N 90 92 93 HO OH HO HO O HO O

HO O OH HO O OH HO OH O Cl O 96 H2N O N OH OH HNH HO OH NGVCCGYKLCHOC 97 O CH3 94 OH

OH 95 CO2H

OH

HO H3C OH CH3 H3C 98 99 H3C CH3

543 (Astellas). GlaxoSmithKline by 2009 have discontinued devel- lipstatin, isolated from bacterium Streptomyces toxytricini, and is opment of remogliflozin etabonate (KGT-1681, 109), a SGLT-2 used to treat the obesity [176]. The antihypertensive angiotensin- inhibitor licensed from Kissei Pharmaceutical. Taisho Pharmaceu- converting enzyme (ACE) inhibitors (e.g. captopril, ramipril and tical in October 2008 announced for discontinuation of TS-033, an quinapril) are derived from the snake venom peptide teprotide. investigational compound for treatment of diabetes [175a].Ason Ilepatril (AVE-7688, 110), is an endopeptidase inhibitor (NEP) May 2009, Astellas have discontinued the development of YM-543 currently in Phase IIb/III trials by sanofi-aventis against hyperten- for the treatment of type 2 diabetes [175b]. sion while in Phase II development for diabetic nephropathy [177]. Migalastat (AmigalÔ, AT1001, 1-deoxygalactonojirimycin, 6. Cardiovascular and metabolic diseases 1-deoxygalactostatin, 111)wasfirst reported by semi-synthesis from galactonojirimycin (galactostatin) 112 isolated from Strepto- NPs have made a major impact in the treatment of cardiovas- myces species. Migalastat is a pharmacological chaperone that Ò cular and metabolic diseases. Simvastatin (Zocor , Merck & Co), enables the restoration of correct folding by stabilizing the protein a hypolipidemic drug belonging to the class of statins, is a synthetic structures through binding with them. In May 2006, orphan derivate of Aspergillus terreus fermentation product and is known to designation was granted by the European Commission to Amicus exert the lipid-lowering activity through inhibition of 5-hydroxy-3- Therapeutics for use of 111 against Fabry disease, which was methylglutarylcoenzyme A (HMG-CoA) reductase. Orlistat, a potent transferred to Shire Pharmaceutical in June 2008. As of January natural inhibitor of pancreatic lipases, is the saturated derivative of 2010, AmigalÔ is in Phase III trials as monotherapy by Amicus B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807 4787

Therapeutics in conjunction with Shire Pharmaceuticals for the a purified cardiac glycoside isolated from the foxglove plant Digi- treatment of Fabry disease [178]. talis lanata [185a] and also occurs in the human adrenal gland and Isofagomine (PliceraÔ,AT2101,113), a synthetic aza-sugar has been considered significant in heart conditions, namely atrial designed to mimic the carbocation transition state used by glyco- fibrillation, and atrial flutter. Rostafuroxin (PST 2238, 121), an sidases [179], was evaluated by Amicus Pharmaceuticals in Phase II ouabain antagonist syntesized by Sigma-Tau, is in Phase II trials for trials against Gaucher’s disease, a lysosomal storage disorder the treatment of chronic arterial hypertension [185bed]. caused by b-glucocerebrosidase deficiency [180a]. In October 2009, Mitemcinal (GM-611, 30-N-dimethyl-11-deoxy-30-N-isopropyl- Amicus disclosed the positive results of Phase II randomized and 12-O-methyl-11-oxo-8,9-didehydroerythromycin, 122) is an orally open-label clinical trial for two dose regimens (225 mg three days administered motilin agonist discovered by Chugai Pharma. on/four days off and seven days on/seven days off) [180b]. Mitemcinal lacks the antibiotic properties of erythromycin and Ruboxistaurin (LY333531, 114), a protein kinase C (PKC) inhib- increases the amplitude & frequency of antral contractions, and itor, was evaluated by Eli Lilly against microvascular complications initiates gastric contractions. Chugai has completed Phase I trials of in diabetes mellitus [181]. In February, 2006, Lilly submitted a NDA 122 in Japan while Phase II trials in US are ongoing for the treat- for 114 in diabetic peripheral retinopathy. In August 2006, Lilly ment of diabetic reflux oesophagitis, and idiopathic gastroparesis received an “approvable” letter from the FDA with a request of [186]. Mitemcinal is also under Phase II trials by Chugai for treat- another Phase III trial for additional efficacy data but no new clin- ment of the irritable bowel syndrome (IBS). ical trials are running. Pyridoxamine (PyridorinÔ, 123) is a vitamin B6 analog based SCH 530348 (TRA, 115), an oral thrombin receptor (PAR-1) on a pyridine ring bearing hydroxyl, methyl, aminomethyl, and antagonist [182a] based on himbacine 116, isolated from the plant hydroxymethyl substituents [187a]. BioStratum have evaluated Galbulimima baccata, is under clinical development by Schering- 123 in two Phase II trials, and observed significant retardation in Plough to prevent atherothrombotic events in patients with ACS, the progression of diabetic nephropathy. In KK-A(y)/Ta mice MI, stroke, or disease of peripheral arteries [182b,c]. SCH 530348 is model, 123 improves the urinary albumin/creatinine ratio though in Phase III clinical development against cardiovascular diseases inhibition of advanced glycation end products (AGEs) and anti- such as atherosclerosis, ischemia, myocardial infarction and stroke. oxidant effects in the kidneys. In October 2006, BioStratum Trodusquemine (MSI-1436, 117), a sulfated aminosterol isolated licensed the programme to NephroGenex. Currently, Neph- from Squalus acanthias (dogfish shark) along with squalamine 118 roGenex has initiated a new Phase IIb clinical trial (PYR-210) for and other steroids [183a], is in clinical development by Genaera safety and efficacy assessments of 123 in slowing the progression Corporation for the treatment of type 2 Diabetes. MSI-1436 is of nephropathy in patients with type 2 diabetes [187b]. Taisho a potent appetite suppressant (protein tyrosine phosphatase 1B Pharmaceutical is evaluating 123 (coded as K-163) in Phase II inhibitor) [183b,c] that causes weight loss without metabolic trials against diabetic nephropathy. In January 2009, the FDA ruled rebound, and normalize fasting blood glucose, blood cholesterol, for regulation of 123 as a pharmaceutical drug, and awarded it and triglyceride levels in obese animals. Genaera is currently with a fast track drug designation. evaluating 117 as an IND in a second Phase I trial against obesity using an ascending single dose in overweight type 2 diabetes. 6.1. Halted or discontinued compounds in cardiovascular and Ouabain (g-strophanthin, 119), is among some cardiac glyco- metabolic diseases sides found in the ripe seeds of Strophanthus gratus, and the bark of þ þ Acokanthera ouabaio. Ouabain can inhibit the Na /K -ATPase of 1-Deoxynojirimycin (AT2220, moranoline, 124) is obtained by plasma membrane especially at the higher concentrations attain- catalytic hydrogenation or borohydride reduction of antibiotic able in vitro or with intravenous dosage [184]. Digoxin 120 is nojirimycin 125 (isolated from Streptomyces species) [188]. Later, 4788 B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807

H

H H N N R N HO CO H O 2 O OH NH HO OH HO H3C OH OH SAc 111 H C 110 R=H 113 3 112 R=OH H N O O O H H H O H H N O CH3 O O O

H C H H H H N N 3 H3C

H C N 3 N O CH3 N H3C CH3 114 115 116

F H3C OSO3H CH3 117 R= H CH3 N NH2 CH3 H H C 118 R=HH 3 H H H N R N N OH H H H O O O

CH3 OH CH HO 3 CH H O HO H 3 O HO H H OH OH CH3 H H OH HO HO H H3C 119 121 CH H O O 3 OH H C H OH OH H C H3C 3 3 O OH O O O HO O O H 120 CH OH OH 3 OH H3C CH H C 3 NH2 3 O H3C H3C O O CH3 N CH3 HO H3C HO OH O O O CH3

CH3 O O OCH3 H3C N 123 CH3 CH3 122 O OH CH3 B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807 4789

Yagi and co-workers isolated 124, which they called moranoline, the mTOR inhibitor sirolimus 10 was developed and successfully a NP occurring in the root bark of various Morus species and evaluated by Isotechnika in Phase I trials against transplant rejec- microorganisms [189]. Amicus launched the Phase II trials for 124 tion [193c]. in June 2008 against Pompe disease [190a,b]. In February 2009, Eupatilin 129 is a pharmacologically active flavone derived Amicus put the development on hold by suspending enrollment for from Artemisia argyi, a Korean traditional medicine significant for the Phase II trials [190c]. In September 2009, Amicus Therapeutics chronic diarrhea [194a]. Dong-A Pharmaceutical are evaluating announced that they are planning to initiate a Phase I trial for DA-6034 130, a synthesized analog of eupatilin 129, in various pharmacokinetic studies of 124 in muscle tissues of healthy adults. Phase I and Phase II trials to use in the treatment of dry eye and The FDA has agreed for proposed Phase I study by Amicus and kept gastritis, respectively [194b]. The synthetic isoflavone derivative 124 on a partial hold [190d]. NV-52, a thromboxane synthase (TXS) inhibitor is being developed MC-1 (pyridoxal 5-phosphate, 126), a naturally occurring as a treatment for inflammatory bowel diseases by Novogen. vitamin B6 metabolite and P2X receptor antagonist, was success- Novogen have completed Phase IIa and IIb trials and found that fully evaluated in Phase II trials as monotherapy as well as in once-daily dosaging of NV-52 has demonstrated no detectable combination with angiotensin blocker lisinopril (coded MC-4232) side effects. Novogen also have NV-07a in Phase II trials for anti- by Medicure for the treatment of chronic cardiovascular, and aging as well as for protection of human skin from sunlight- metabolic diseases [191]. In March 2008, Medicure couldn’t met the induced damage [194c]. end point in a Phase III trial of 126 to acertain the effects on cardiovascular death combined with nonfatal myocardial infarc- 7.1. Halted or discontinued compounds in immunological and tion. Currently, Phase II trials of 126 for the treatment of chronic inflammatory diseases cardiovascular disease, and Phase III trials for Coronary Artery Bypass Graft Surgery (CABG) by Medicure are on clinical hold. Fingolimod (FTY720, 131) is an immunosuppressant agent Medicure is now planning for a Phase II trial of 126 in lipid lowering derived from fungal metabolite myriocin 132 isolated from fungus during metabolic syndrome, a group of symptoms that promote Isaria sinclairii [195]. Fingolimod 131 produces immunosuppressant coronary artery disease, stroke, and type 2 diabetes [192]. activity after phosphorylation in vivo by sphingosine kinase to yield an active metabolite that is a potent agonist of sphingosine-1- phosphate (S1 P) receptors 1, 3, 4 and 5 [196]. Novartis and Mit- 7. Immunological, inflammatory and related diseases subishi Tanabe were evaluating 131 for the treatment of multiple sclerosis in US & European Phase III and Japanese Phase II trials. In Autoimmune diseases are the results of overactive immune a Phase III clinical trial in kidney transplantation, the drug 131 was response of the body against substances and tissues. This may be found to be no better than the existing standard of care. Both localized to certain organs or particular tissue affecting the base- Novartis and Mitsubishi Tanabe have discontinued clinical devel- ment membrane of lung and kidney. Aspirin, a NPs derived opment of 131 for transplantation. compound discovered in the late 1890s is still being used as an Ancrod (ViprinexÔ), a defibrinogenating agent which binds analgesic and anti-inflammatory drug. Salbutamol is a short-acting with high specificity to fibrinogn [197a], was extracted from b2-adrenergic receptor agonist marketed by GlaxoSmithKlinen for Malayan pit viper venom. In January 2005, fast-track status was relief of asthma and chronic obstructive pulmonary disease. given to ViprinexÔ by the FDA for treatment of acute ischemic The launch of NPs, e.g., cyclosporin 74 (1983), tacrolimus (1993), stroke, a condition that arises due to blockage of blood vessels sirolimus 10 (1999) and mycophenolate sodium (2003), and the supplying brain. Neurobiological Technologies have evaluated semi-synthetic NPs mycophenolate mofetil (1995) are surving as ViprinexÔ in various Phase III trials, which failed to show benefits significant immunosuppressive drugs. Everolimus (LuveniqÔ or in patients suffering from acute ischemic stroke [197b]. In January LX211, 127), an mTOR inhibitor and derivative of 10 is marketed as Ò 2009, Neurobiological Technologies have suspended the ViprinexÔ immunosuppressant by Novartis under the trade names Certican development program and have decided not to develop it further in organ transplantation. for the treatment of acute ischemic stroke [197c]. Voclosporin (ISA-247, R1524) 128, a calcineurin inhibitor [193a] and semi-synthetic derivative of cyclosporine-A 74, is in a Phase IIb 8. Oncological diseases trial to prevent the rejection of kidney graft while in Phase III development against psoriasis. Isotechnika has licensed 128 to Lux 8.1. Small-molecule anticancer agents Biosciences for ophthalmic indications. In March 2009, the three Phase III trials for 128 (coded LX211) oral capsules against uveitis 8.1.1. Plant-derived compounds were completed successfully by Lux Biosciences. In February 2010, Camptothecin 133, a quinoline based cytotoxic alkaloid isolated Lux Biosciences filed a NDA with the FDA and a MAA with the EMA from the bark and stem of Camptotheca acuminata [198], shows for 128, under LuveniqÔ to use in the treatment of non-infectious significant anticancer activity through inhibition of topoisomerase uveitis involving the posterior eye segment, which were accepted Ò I. BioNumerik are developing Karenitecin (BNP-1350, 134)asan by respective agencies in March 2010 [193b]. TAFA-93, a prodrug of investigational anti-tumor agent among camptothecin class of chemotherapy drugs [199]. In February 2008, BioNumerik Phar- H maceuticals have initiated the Phase III clinical trial of 134 in CHO O N R OH advanced ovarian cancer patients [200].Diflomotecan (BN80915) HO HO P 135, an analog of 134, is currently under Phase II clinical develop- OH O ment by Ipsen against advance metastatic cancers [201].In HO OH November 2003, Novartis gained rights to develop and commer- cialize (ST-1481, 136) from Sigma-Tau as an oral topoisomerase I OH H3C N 124 R=H inhibitor. Gimatecan is currently in Phase II development to use in 125 R=OH 126 treatment of solid tumors [202]. Elomotecan (BN-80927, LBQ707, R-1559, 137), a cytotoxic agent inhibiting topoisomerase I and II, is being evaluated by Ipsen against certain advanced metastatic 4790 B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807

cancers (e.g. colon, breast and prostate) [203]. As of April 2009, 137 Combretastatin A-4 phosphate (ZybrestatÔ, CA4P, 140)is is a promising Phase I pipeline by Ipsen in oncology. DRF 1042 138, a prodrug of combretastatin A-4 141, a most potent among the is an orally active camptothecin derivative that was evaluated by Dr. combretastatin class of natural stilbenoid phenols obtained from Reddy’s Laboratories in Phase I trials for the treatment of various Combretum caffrum, South African Bush Willow [206]. Com- cancers [204]. In September 2006, Dr. Reddy’s Laboratories bretastatin A-4 141 acts as a reversible tubulin depolymerizing collaborated with ClinTec International for development of 138 in agent and causes tumor-associated endothelial cells to change from Phase II/III trials. SN2310 139, an injectable prodrug of SN-38 140,is a flat to a round shape, thus plugging the blood vessels, and currently in Phase I clinical trial for safety, pharmacokinetics and deprives the tumor from oxygen and nutrients [207]. Oxigene are tolerance accessment in cancer patients. In September 2006, Sonus evaluating 140 as a vascular disrupting agent (VDA) in various initiated a Phase I study of 139 which is presently ongoing, and after Phase I/II/III trials [208]. As on September 2008, 140 is under Phase merger of Sonus Pharmaceuticals with OncoGenex Technologies in III trial against anaplastic thyroid cancer (ATC). In November 2009, May 2008, the new company, OncoGenex Pharmaceuticals have Oxigene announced for positive results from Phase II trial of 140 in listed 139 in oncology pipeline to address cancer [205]. non-small cell lung cancer (NSCLC) [209a]. Ombrabulin (AVE8062) 142, another water soluble derivative of 141 was licensed to Sanofi- Aventis from Ajinomoto, is under Phase III trials in advanced soft tissue sarcoma (STS) patients [209b]. CH 3 Combretastatin A-1 diphosphate (OXi4503, 143), a pro-drug of HO combretastatin A-1 144, is metabolized by oxidative enzymes that 131 fi NH2 are present in various solid and liquid tumors and tumor in ltrates HO OH resulting in the creation of reactive oxygen species (ROS) and an orthoquinone metabolite which covalently binds to proteins and

HO CH3 nucleic acids (DNA), causing direct cytotoxic effects on tumor cells HO2C [210]. OXGENE are evaluating 144 in various Phase I trials against NH2 OH O advanced-stage solid tumors. Noscapine (CB3304, noscapine, 145), 132 a microtubule targeting antitussive benzylisoquinoline alkaloid isolated from plants of the Papaveraceae family, is currently under B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807 4791

Phase I/II trials by Cougar Biotechnology against multiple myeloma, opinion with recommendation for marketing authorization of 147 a cancer of plasma cells [211]. in the metastatic treatment of bladder cancer [214b]. Ò Ò Vinblastine (Alkaban-AQ , Velban , 146), a vinca alkaloid first Paclitaxel (TaxolÔ, AbraxaneÔ, 148) [215a], a mitotic inhibitor isolated from Catharanthus roseus [212], inhibits the assembly of used to treat patients with lung, ovarian, breast cancer, head and microtubules by binding to tubulin. An intravenous injection of 146 neck cancer, and advanced forms of Kaposi’s sarcoma, was isolated is significant against non-Hodgkin’s lymphoma, Hodgkin’s disease, originally from Taxus brevifolia. Paclitaxel 148 stabilizes microtu- Kaposi’s sarcoma, TCL, breast, testicular, lung, neck and head bules and interferes with the normal breakdown of microtubules cancers and choriocarcinoma [213]. The fluorinated vinca alkaloid, during cell division [215b]. Bristol-Myers Squibb (BMS) are associ- Ò vinflunine (Javlor , 147) [214a] was licensed by Bristol-Myers ated with commercial development of 148. Squibb from Laboratoires Pierre Fabre that was terminated in Sanofi-Aventis have designed cabazitaxel (XRP6258) 149 and November 2007. In June 2008, after positive Phase III trial in the larotaxel (XRP9881) 150 as poor substrates for membrane- metastatic treatment of bladder cancer, 147 was submitted for associated P-glycoprotein (P-gp), since overexpression of P-gp is registration with the EMEA by Laboratoires Pierre Fabre. In June crucial in taxane resistance [216]. Cabazitaxel 149 and larotaxel 150 2009, Laboratoires Pierre Fabre announced for receiving a positive are currently in a Phase III trials to use in the treatment of patients

R

H3C O F N O N N N F N H C O 3 O H C O 133 R=H 3 N H3C 134 R= HO O O Cl N HO Si(CH3)3 O 135 137 136 R= N C(CH ) H3C O 3 3 O CH3 CH CH CH HO 3 3 3 CH H3C O 3 O H3C O CH3 OH O O CH O O 3 O N N N 139 N O O H3C NH2 138 H N HO HO O H3C O R OR O OH OR OCH3

OCH3 H3CO OCH3 OCH3 H CO OCH 3 3 OCH3 142 143 R=PO3Na2 OCH H CO OCH 3 3 3 144 R=H 140 R=OPO3Na2 OCH3 141 R=OH F OH H F O N CH H N CH3 3 N O CH3 H N O H N O H3C N N H H CH CH3 3 H CO C OH O H3CO2C OH 3 2 N OAc H CO N OAc H3CO H3C O O CH3 3 H H CH CO CH CH3 CO2CH3 3 2 3 145 146 147 4792 B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807 with pancreatic and hormone-refractory prostate cancers [217]. patients with advanced malignancies are currently in Phase II Ò DHA-paclitaxel (Taxoprexin ) 151, a fatty acid conjugate of pacli- clinical development [224]. taxel 148, is currently under pivotal Phase III trial by Luitpold Acronycine 157, an alkaloid isolated in 1948 from the stem bark Pharmaceuticals against metastatic melanoma [218]. Spectrum is of a Australian Rutaceous tree, Acronychia baueri, displays activity evaluating a third generation intravenously as well as orally avail- against a panel of murine solid tumor models, including S-180 and able taxane, ortataxel (IDN-5109, BAY-59-8862, 152) [219] having AKR sarcomas, X-5563 myeloma, S-115 carcinoma and S-91 mela- similar toxicity/tolerance profile to paclitaxel 148 in Phase I/II trials. noma [225]. A benzoacronycine derivative S23906-1 158 shows Ò Ortataxel 152 displays activity in tumors resistant to Taxol and as antineoplastic activity by inhibition of DNA synthesis and also of June 2009, the drug is in Phase II trials in taxane-refractory solid causes an irreversible S-phase blockage in the cell cycle and effi- tumors [220]. Milataxel (MAC-321, TL-00139) 153, an orally ciently triggeres apoptosis in several cancer cell types. Currently, bioavailable taxane and poor substrate for P-gp is under Phase II Laboratories Servier are evaluating 158 in various Phase I trials clinical development by Wyeth Pharmaceuticals to use in the against solid tumors [226]. Ò treatment of colorectal neoplasms [221]. Homoharringtonine (omacetaxine mepesuccinate, Ceflatonin , Tesetaxel (DJ-927, 154), an orally bioavailable semi-synthetic 159), a myelosuppressive alkaloid originally isolated from the taxane that was evlaulated by Genta in various Phase I/II trials in evergreen tree Cephalotuxus fortuneii, inhibits synthesis of Mcl-1 patients with advanced gastric and breast cancer [222]. A Phase II protein and induces apoptosis [227a]. In October 2004, the Euro- clinical trial of 154 is undergoing in advanced melanoma patients pean Commission granted orphan designation to Stragen France with a normal serum lactate dehydrogenase (LDH) and have pro- SAS for 159 against acute myeloid leukemia (AML). In January 2009, gressed after one chemotherapy regimen. Genta are also planning sponsorship was transferred to ChemGenex Europe SAS, France. In to explore the activity of 154 in advanced castrate-resistant pros- January 2009, an Orphan Drug designation was given to 159 by the tate cancer (CRPC). Other taxanes, i.e. TPI-287 155 by Tapestry FDA to use in the treatment of myelodysplastic syndromes (MDS). Pharmaceuticals for the treatment of advanced pancreatic cancer In September 2009, ChemGenex submitted a NDA for 159 under [223], BMS-188797 156 by Bristol-Myers Squibb for treatment of OmaproÔ (omacetaxine mepesuccinate) to the FDA for the

CH3 O CH3

O CH3 H3C O H CO O 3 O O NH O H3C CH3 CH OH O NH O H3C 3 CH3 O CH3 CH O 3 CH O 3 H CH OH 3 H OH HO 148 O O O 149 HO O O O O O O H C O 3 H3C CH3 CH 3 O O O CH3 H3C O O H3C O H3C O O NH O O NH O H3C CH3 OH CH3 CH3 O O CH3 CH H 3 H OH OR HO 150 O O HO O O O O 151 O O O O H3C O H3C

R= 6 CH3

CH3 O CH3 CH3 CH3 O CH3 H3C O CH O 3 H3C O O OH H3C O NH O CH O 3 OH NHO O H C 3 CH O CH3 3 O CH CH 3 3 H O OH CH3 O H H3C CH3 O OH O O O O HO O O O 152 O O 153 O O O H3C H3C B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807 4793 treatment of chronic myelogeneous leukemia (CML) patients who Epipodophyllotoxin (F11782, 162), a naturally occurring non- have a particular gene mutation (T315I mutation) or failed in alkaloid extracted from root of Podophyllum peltatum [231a],is imatinib therapy. In March 2010, Oncologic Drugs Advisory a non-intercalating dual inhibitor of both topoisomerases I and II Committee of the FDA recommended for validated test to identify that impairs the binding of the enzyme to DNA, but does not the T315I mutation prior to approval of OmaproÔ [227b]. Chem- stabilize the cleavage complex [231b].Tafluposide 163 is a deriva- Genex are also evaluating 159 in Phase II clinical trial to use in the tive of 162 and is currently in Phase I clinical development for anti- treatment of patients with refractory or relapse AML who have tumor activity by Pierre Fabre [232]. failed intensive chemotherapy. Ingenol 164, extracted from the sap of Euphorbia peplus is under 30-O-methyl-nordihydroguaiaretic acid (NDGA) 160, a lignan clinical development by Peplin Biotech for topical treatment of originally isolated from the creosote bush Larrea divaricatta is certain skin cancers, such as basal cell carcinomas and squamous known to exhibit significant antipromoter, anti-inflammatory, and cell carcinomas [233]. In November 2009, Peplin merged with LEO antineoplastic activities. NDGA 160 probably inhibits activation of Pharma. Peplin’s oncology lead, ingenol mebutate (PEP005, 165), insulin-like growth factor receptor (IGF-1R) and the c-erbB2/HER2/ a PKC activator and derivative of 164, is currently in Phase III clinical neu receptor, causing retardation in tumor cell proliferation [228]. development against actinic keratosis (AK). In December 2009, LEO Terameprocol 161, a transcription inhibitor and synthetic derivative Pharma announced the positive results of 165 in two Phase III trials of 160, was licensed to Erimos by The Johns Hopkins University to for the treatment of AK lesions on head, including the face and use in oncology. Terameprocol 161 induces apoptosis in cancer cells scalp. In February 2010, LEO Pharma disclosed to meet the primary by inactivation of maturation promoting factor (CDC2/cyclin B end point with disappearance of AK lesions in non-head locations complex) and survivin production and phosphorylation [229]. Eri- during a Phase III study [234]. mos are evaluating 161 in various Phase I/II trials against solid Daidzein 166, an isoflavone occurring in a number of plants and tumors, glioma and leukemia [230]. herbs including Pueraria Mirifica, soybeans and soy products,

CH 3 CH3 CH3 N O CH CH 3 CH3 3 CH O CH O 2 O 3 NHO O H3C CH O CH3 3 H3C O N CH3 O O CH O NH O H3C O 3 H CH3 OH CH3 F HO O CH O O 3 H 154 O OH O H3C CH3 HO O OCH3 O 155 O O H3C O O O H C O 3 N O CH 3 OH CH3 R H3C O H3C CH3 CH3 O O NH O H3C R CH3 OH

CH3 157 R=H O 158 R=OAc CH OH 3 H OH O HO OCH 156 O O 3 H3C CH3 O H3C O O O O F F O H3CO O H F O N F O F F H3CO OR F F O O 159 OR OR H3C O O 160 R=H O F CH3 CH 161 R = CH3 O O F 3 O O O H3C OH O O O H3C O O H O HO O RO HO H O HO

H3CO OCH3 164 R=H OCH3 O OH H CO OCH P 3 3 OH 165 R= OCH3 O CH3 162 163 4794 B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807 exhibits clinical indication against tumors [235]. Novogen are Curcumin 175 is under various world wide Phase I/II trials while evaluating a series of synthetic analogs of 166 in various preclinical a Phase III trial in patients with MCC is underway. and clinical trials to use in the treatment of caners. Phenoxodiol 167 RTA 402 (CDDO-Me, Bardoxolone methyl, 176) a synthetic tri- [236], a synthetic analog of 166, was licensed by Marshall Edwards terpenoid analog of oleanolic acid 177, occurring naturally in various from Novogen for development as a chemosensitizing agent in food and medicinal plants [244a], is being evaluated by Reata combination therapy with platinum drugs against chemoresistant Pharmaceuticals in under Phase I/II clinical development against ovarian cancer and also as a monotherapy to use in the treatment of prostate cancer and Phase II trials in type 2 diabetes with chronic prostate and cervical cancers. Phenoxodiol 167 is supposed to kidney disease (CKD). RTA 402 176 potently inhibits the activation of inhibit selectively S-1-P (sphingosine-1-phosphate), the overex- IkB alpha kinase (IKK) associated with suppression of nuclear factor pressed pro-survival regulator and makes cancer cells more sensi- kappa-B (NF-kB) dependent genes that prevent apoptosis, promote tive to chemotherapy. Phenoxodiol 167 is under Phase III proliferation and angiogenesis [244b]. In October 2008, an orphan investigations by Marshall Edwards to restore chemosensitivity in drug designation by the FDA was granted to 176 against prostate patients with ovarian cancer resisting platinum drugs. A Phase II cancer. In January 2010, Reata Pharmaceuticals have given exclusive trial of 167 in patients with castrate and noncastrate prostate rights to Kyowa Hakko Kirin for development and commercializa- cancer is also underway [237]. Triphendiol (NV-196), an orally- tion of 176 in Japan and other selected Asian regions for treatment of delivered chemosensitizing derivative of 167 that was licensed to type 2 diabetes suffering from CKD [244c]. Marshall Edwards by Novogen, is under Phase I trials for use in Betulinic acid (ALS-357) 68, a pentacyclic triterpenoid isolated combination therapy against cholangiocarcinoma, advanced pros- from white birch (B. pubescens), was evaluated in preclinical studies tate cancer and melanoma. An orphan drug status was granted to by Advanced Life Sciences where it demonstrated specific anti- 167 by the FDA for cholangiocarcinoma, prostate cancer and stage tumor activity against malignant melanoma (MM). ALS-357 68 IIb-IV malignant melanoma. In January 2009, FDA granted IND has a unique mechanism of action that disrupts mitochondrial approval to 167. Genistein 168, a soy-derived antineoplastic phy- membrane function and is associated with the intrinsic, toestrogen, inhibits protein-tyrosine kinase and induces cell mitochondria-mediated pathway of apoptosis [245]. ALS-357 68 differentiation, is under Phase I/II trials by Astellas, Bausch & Lomb has orphan drug designation by the FDA for topical treatment of for treatment of tumors. Genistein 168 is also supposed to inhibit MM and is currently in Phase I clinical development by Advanced topoisomerase II, resulting in DNA fragmentation and apoptosis. Life Sciences. Silybin 178,aflavonolignan extracted from blessed Gossypol 169, a polypenolic aldehyde extracted from cottonseed milk thistle (Silybum marianum) and the active constituent of IdB Ò plant of genus Gossypium, family Malvaceae, acts as an inhibitor for 1060 (silybin-phosphatidylcholine complex, Siliphos ), is currently several dehydrogenase enzymes [237]. Ascenta Therapeutics are in Phase II clinical development by American College of Gastroen- developing ()-gossypol (AT-101,169) as an orally-active, pan-Bcl-2 terology for cancer chemoprevention [246]. inhibitor that causes apoptosis in cancer cells through working as BH3 mimetic. In June 2009, Ascenta Therapeutics announced the 8.1.2. Microorganism-derived compounds promising results of Phase I/II study of 169 in prostate, brain and 8.1.2.1. Actinomycetes. Pladienolide D 179, discovered as bioactive lung cancers. In October 2009, Ascenta Therapeutics announced the compounds in Streptomyces platensis Mer-11107 fermentation results of a Phase I trial for two combination regeims containing 73 broth, exerts potent antiproliferative activities against a wide in patients with malignant brain tumor [238]. variety of cancer cell lines [247a,b].E7107180 is a synthetic ASA 404 (vadimezan, AS1404 and DMXAA, 170), a derivative of urethane derivative of 179 that binds with spliceosome-associated flavone-8-acetic acid 171, was discovered originally at Auckland protein 130 (SAP130) and inhibits the splicing of pre-mRNA Cancer Society Research Centre. The flavonoid 171 works as resulting in cell cycle arrest [247c]. Eisai are evaluating 180 in a tumor-VDA that was in-licensed by Antisoma in 2001 [239].In Phase I trials against solid tumors. April 2007, Novartis AG signed an agreement with Antisoma for Chartreusin (U-7257, 181) and elsamicin A (BMY-28090, elsa- worldwide rights and co-selling of 170 in the US. As on April 2008, mitrucin, 182) are the antibiotics having similar structures and both after a positive Phase II trial, 170 is currently in Phase III clinical inhibit RNA synthesis and result in single-strand scission of DNA. development by Novartis as a second line treatment for NSCLC. Chartreusin 181 was originally isolated from the culture broth and A second Phase III trial for 170a as first line treatment for NSCLC mycelial cake of Streptomyces chartreuses. Elsamicin A 182 that has been discontinued in March 2010 [240]. b-Lapachone (ARQ- bears chartarin chromophore but differ in sugar moieties i.e. bears 501, 172), a naphthoquinone derived from Tabebuia avellanedae, an amino sugar, was isolated from actinomycete strain J907-21 in exerts anti-tumor effect by a rapid and sustained increase of the 1986 [248]. Elsamicin A 182 is also a potent inhibitor of top- pro-apoptotic protein E2F-1, as well as induces expression of oisomerase I and II, enzymes that play an important role in DNA cyclin dependent kinase inhibitor 1A (CDKN1A or p21) [241a]. replication. Elsamicin A 182 is under Phase II clinical trials by ArQule are currently evaluating 172 as a combination therapy in Spectrum Pharmaceuticals for treatment of patients with advance Phase II trials to treat pancreatic and ovarian cancer [241b,c]. solid tumors. Ò Alvocidib (Flavopiridol, HMR 1275, 173) a synthetic derivative of Doxorubicin (Adriamycin ) 183, an anthracycline antibiotic rohitukine 174, isolated from Dysoxylum binectariferum [242a],is originally isolated from bacteria found in soil samples taken from being developed by Sanofi-Aventis as their oncology pipeline in Castel del Monte, an Italian castle, is a DNA intercalating drug collaboration with NCI. Alvocidib 173 is a CDK inhibitor [242b] that commonly used against a wide range of cancers, including hema- prevents phosphorylation of CDKs and by down-regulating cyclin tological malignancies, many types of carcinoma, and soft tissue D1 and D3 expression results in G1 cell cycle arrest and apoptosis. sarcomas [249a]. L-annamycin 184 was originally developed at the As on May 2009, 173 is under late Phase III oncology pipeline by M D Anderson Cancer Center while studies on clinical limitations Sanofi-Aventis to use in the treatment of NSCLC patients while in with anthracycline drugs. Doxorubicin 183 has orphan drug status Phase IIb for patients with chronic lymphocytic leukemia [242c]. by the FDA to use in the treatment of acute lymphocytic leukemia Curcumin 175, a polyphenol extracted from roots of Curcuma (ALL) and AML. L-annamycin 184 inhibits topoisomerase II and is longa (a popular Indian spice of family Zingiberaceae), has been currently in Phase I/IIa trials by Callisto Pharmaceuticals in adults considered significant against metastatic colon cancer due to its with ALL as well as younger adults with refractory or relapsed ALL ability to interfer with the p53 tumor suppressor pathway [243]. or AML [249b]. Berubicin (RTA744, WP744, 185) is an anthracycline B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807 4795

that intercalates with DNA and inhibits DNA replication by binding species [255a], can bind with heat shock protein 90 (HSP90) playing with topoisomerase II, is able to cross the blood brain barrier, hence crucial role in apoptosis, angiogenesis and oncogenesis [255b,c]. finds significance in the treatment of primary brain tumor. In Tanespimycin (17-AAG, KOS-953, NSC-330507, 191) is a compara- October 2006, orphan drug designation to 185 was granted by the tively less toxic derivative of 190 and exerts anti-melanoma effect by FDA against malignant gliomas. Reata Pharmaceuticals are binding to HSP90 and interrupts the MAPK pathway [256].Ason currently conducting Phase II clinical trials of 185 for treatment of November 2009, a Phase II/III randomized open-label trial of 191 in Ò malignant gliomas. Sabarubicin (MEN-10755, 186), a topoisomerase combination with Velcade in relapsed-refractory multiple II inhibitor [250a] and disaccharide analog of 183, is currently in myeloma patients has been completed by Kosan. Alvespimycin (17- Phase II clinical trial by Menarini Pharmaceuticals against solid DMAG, KOS-1022, NSC-707545,192) developed by Kosan as a second tumors [250b,c]. Sabarubicin 186 is also being evaluated as generation HSP90 inhibitor [257] is under clinical development for combination therapy with cisplatin against small-cell lung cancer treatment of solid tumors. As of January 2008,192 is being evaluated (SCLC). Nemorubicin (MMDX, PNU-152243A, 187)a30-deamino-30 as combination therapy in a Phase I trial with trastuzumab & pacli- Ò [2-(S)-methoxy-4-morpholinyl] derivative of 183, is a DNA- taxel (Taxol ) against solid tumors, Phase II trial as monotherapy intercalator and potent inhibitor of topoisomerase I, shows against HER2-positive metastatic breast cancer and Phase I trial activity on selected tumors resistant to current treatment. Nem- against solid tumors. Retaspimycin (IPI-504, 17-AAG hdroquinone orubicin 187 is currently in Phase I/II trials by Nerviano Medical salt, 193) is a HSP90 inhibitor that is under Phase I/II clinical devel- Sciences [251]. opment by Infinity Pharmaceuticals as a single agent and in Distamycin A 188 is the lead compound of brostallicin (PNU- combination with existing drugs against certain cancers [258]. 166196) 189 that was originally developed by Nerviano as a DNA Infinity is currentlyconducting a Phase II clinical trial of 193 in NSCLC minor grove binder (MGB) which retains sensitivity in DNA patients, while also enrolling patients for another Phase II trial to Ò mismatch repair-deficient tumor cells [252].Thea-bromoacrylic evaluate 193 in combination with Herceptin in patients with HER2 moiety of 189 appears to reacts with GSH, in a reaction catalyzed by positive metastatic breast cancer [259]. GST, with the possible formation of a highly reactive GSH-complex The mTOR inhibitor, deforolimus (AP23573, MK-8669, 194)is able to bind covalently to DNA [253]. Nerviano had transferred the being co-developed by Merck and ARIAD Pharmaceuticals for the exclusive world right of 189 to Systems Medicine Inc. that has now treatment of several tumor types including sarcoma [260].InMay been taken over by the Cell Therapeutics. Cell Therapeutics are 2009, ARIAD have changed the name of 194 form ‘deforolimus’ to currently evaluating 189 in a Phase II trial as monotherapy in patients ‘ridaforolimus’, and the same was adopted by the United States with advanced or metastatic soft tissue sarcoma (MSTS), and in Adopted Name (USAN) Council. Ridaforolimus 194 has fast-track a context of vulnerability trial in several patient populations [254]. and orphan drug designation by the FDA and orphan drug status Geldanamycin 190, a benzoquinone ansamycin antibiotic origi- by the EMEA against soft tissue and bone sarcomas. In December nally discovered in the broth and the mycelium of Streptomyces 2009, ARIAD Pharmaceuticals completed the enrollment for 4796 B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807

a Phase III study of oral 194 in patients with metastatic soft tissue [266]. PKC-412 198 inhibits several protein kinases including FLT3 and bone sarcomas. Besides, ARIAD are also running several Phase and is highly anticipated as a potent therapeutic agent for Phase II I/II trials to evaluate 194 as a single agent and in combination trials in AML patients carrying FLT3 mutations. therapies [261]. K252a 199, an alkaloid isolated from soil fungi of Nocardiopisis Salinosporamide A (NPI-0052, 195), possessing a g-lactam-b- species, is a staurosporine analog and the lead compound of les- lactone bicycle is produced by a marine bacterium Salinispora taurtinib (CEP-701, KT-5555, 200) that inhibits FLT3 [267a] and tropica [262a]. Salinosporamide A 195 is a proteasome inhibitor tyrosine phosphorylation of Trk A. As of 2008, lestaurtinib 200 is in that exerts activity by modifying the threonine residues of the 20S Phase III clinical trials for AML and Phase II trials for myeloprolif- proteasome [262b]. In May 2006, 195 entered Phase I clinical trials erative disorders. In June 2009, Cephalon disclosed the results from by Nereus against solid tumors and lymphomas. As on April 2008, a pivotal trial of 200 in patients with relapsed AML expressing FLT3 Nereus Pharmaceuticals are enrolling patients for a Phase Ib trial of mutations [267b]. Another staurosporine analog, KRX-0601 (UCN- Ò 195 in combination with vorinostat (Zolinza ) for selected solid 01, KW-2401, 201) inhibiting CDKs, is currently in Phase II clinical tumor malignancies [262c]. trials by Keryx (Kyowa Hakko) under sponsorship of NCI for treat- Staurosporine 196, an alkaloid originally isolated from bacte- ment of melanoma, TCL and SCLC [268]. rium Streptomyces staurosporeus [263a], is the precursor of protein Diazepinomicin (ECO-4601, TLN-4601, 202) is a dibenzodiaze- kinase inhibitors [263b], enzastaurin (LY317615) 196 and mid- pine alkaloid originally isolated from the culture of a marine acti- ostaurin (PKC-412, CGP 41251, 40-N-Benzoyl-staurosporine) 198. nomycete of the genus Micromonospora [269] that binds selectively Enzastaurin (LY317615, 197) is a serine/threonine kinase inhibitor to peripheral benzodiazepine receptor (PBR), resulting in tumor and is under clinical development by Eli Lilly for treatment of apoptosis, and inhibits the Ras/MAP kinase signaling pathway variety of tumor types [264]. In June 2007, Eli Lilly announced the involved in cellular proliferation and migration [269c]. ECO-4601 results of a Phase II clinical trial of 197 in patients with late-stage 202 was found safe and well-tolerated in Phase I/II trial con- NSCLC. As of April 2010, 197 is under Phase III trials against ducted by the NCI and Thallion. In November 2007, Thallion diffuse large B-cell lymphoma (DLBCL) [265]. Midostaurin 198 was demonstrated that 202 can cross the blood brain barrier and targets demonstrated safe in Phase I pharmacokinetic study by Novartis glioblastoma multiforme (GBM). As on September 2008, Thallion B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807 4797

are enrolling patients for Phase II trial of 202 as a second line February 2007, Kosan were planning to initiate Phase II clinical treatment for GBM [269d]. development of 207 against multiple solid tumors in collaboration with Roche. 8.1.2.2. Eubacteria. Prodigiosin (Streptorubin B, 203), a red pigment produced by many strains of the bacterium Serratia mar- 8.1.2.4. Fungi. NPI-2350 (halimide, phenylahistin, 208), a diketopi- cescens [270] and is the lead compound of obatoclax (GX15-070, perazine metabolite consisting of L-phenylalanine and iso- 204), a Bcl-2 inhibitor that is under clinical development by Gemin prenylated dehydrohistidine, was originally isolated from a marine X for treatment of tumors. Gemin X are developing intravenous fungi aspergillus ustus. Plinabulin (NPI-2358, 209), a tubulin- infusion of 204 in multiple Phase I/II trials as a monotherapy in depolymerizing synthetic analog of 208 [275a], is under clinical hematological and solid tumor cancer indications while as combi- development by Nereus. In November 2009, Nereus announced the nation therapy with carboplatin & etoposide in SCLC and with positive results of a Phase II trial of 209 as combination therapy Ò bortezomib (Velcade ) in mantle cell lymphoma (MCL). In March with docetaxel in NSCLC patients [275b]. Irofulven (MGI-114, 2009, Gemin X launched a Phase II study of 204 in combination HMAF, 210), an analog of illudin S 211, a sesquiterpene toxin found with carboplatin & etoposide as first-line treatment SCLC while in mushrooms of the genus Omphalotus [276]. Irofulven 210 inhibits results of a Phase Ib trial of 204 as first line treatment for extensive- DNA synthesis and is currently in Phase II/III development by Eisai stage SCLC was release in May 2009 [271]. (MGI Pharma) in patients with advanced-stage prostate cancer and advanced GI solid tumors. 8.1.2.3. Myxobacteria. Patupilone (epothilone B, EPO-906, 21), microtubule-stabilizing NP produced by the myxobacterium 8.1.3. Marine-derived compounds Ò S. cellulosum, is currently under Phase III trials by Novartis against Plitidepsin (Aplidin , 212), a cyclic depsipeptide extracted from ovarian cancer while Phase II clinical development for the treat- Aplidium albicans, is being evaluated in Phase II clinical trials by ment of other tumor types [272]. Sagopilone (ZK-EPO, ZK-219477, PharmaMar in hematological and solid tumors. Plitidepsin 212 205) is a synthetic derivative of 21 that binds to tubulin and inhibits the vascular endothelial growth factor (VEGF) protein that induces microtubule polymerization [273a] causing inhibition of causes vascularization and growth of tumors. After getting prom- cell division, induction of G2/M arrest, and apoptosis [273b]. Unlike icing results from a multicenter Phase Ib study, PharmaMar are taxanes, 205 is able to retain activity in MDR cancer cells over- currently evaluating 212 under Phase II trials as a first-line mono- expressing the P-gp. As of February 2010, ZK-EPO 205 is in Phase II therapy treatment and in combination with dacarbazine for clinical development by Schering AG against lung, ovarian and advanced unresectable melanoma [277]. prostate cancers [273c]. Halichondrin B 213, isolated from Halichondria okadai sponge Epothilone D (desoxyepothilone B) 206 is a natural polyketide [278a], has been considered significant by NCI as a novel anticancer that inhibits the disassembly of microtubules by binding to agent. Eribulin mesylate (E7389, ER-086526, NSC-707389) 214, tubulin. The 9,10-didehydroepothilone D (KOS-1584, 207) [274], a structurally-simplified and pharmaceutically-optimized analog of a second-generation epothilone derivative of 206 being evaluated 213, is being developed by Eisai as a third-line treatment against by Kosan Pharmaceuticals in multiple solid tumor types. In Phase I advanced breast cancer patients, previously treated with standard dose escalation trials by Kosan, 207 has defined efficacy and cancer chemotheraputics. Eribulin 214 is a microtubule dynamics tolerability against patients with ovarian cancer and NSCLC. As of inhibitor that prevents various cellular processes [278bed].In 4798 B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807

OCH 3H3C OCH3

N N H N N H HN HN 203 204 CH3

H3C

S CH3 CH3 O H3C O O S N OH H3C OH N CH3 H3C H C CH3 3 H3C H3C CH3 O CH2 O O OH O OH

CH3 205 206 S CH3 O H3C O O N OH NH N NH CH3 HN CH2 H C 3 H3C CH3 O O H3C CH OH 3 207 208 CH3 O CH3 OH CH 3 OH NH N NH HN CH3 CH3 OH HO HO CH3 O H3C H C H C 3 3 CH3 O O 209 210 211

March 2010, Eisai submitted regulatory applications to agencies in FDA (2001) and a similar designation by the EU (2002) for use in Japan, US and EU for approval of 214 against locally advanced or combination with TaxolÔ against esophageal cancer. In 2001, the metastatic breast cancer. Hemiasterlin 215, a NP-derived from 219 was licensed by GPC Biotech from Arizona State University and marine sponges [279], inhibits tubulin assembly and disrupts is currently in various Phase I/II trials under guidance of the NCI normal microtubule dynamics and depolymerizes the microtu- [281b,c]. bules. E7974 216, a synthetic analog of 215 that can bind to a and Jorumycin 220, first isolated from the nudibranch Jorunna Ò b tubulin, is under Phase I clinical development by Eisai against funebris [282a], is the lead compound of Zalypsis (PM00104/50) a variety of human tumor xenografts. 221 that was evaluated in Phase I clinical trials by PharmaMar Ò Psammaplin A 217, isolated from the marine sponge Psamma- against solid tumors or lymphoma. Zalypsis 221 exerts cytotoxic plinaplysilla, inhibits the key enzymes that control gene expression, effects dependent on DNA binding that are not associated with DNA DNA replication and angiogenesis. Panobinostat (LBH-589, 218) damage. As on November 2009, 221 is in Phase II clinical trial for a synthetic analog of 217 is being evaluated by Novartis in Phase I as treating cervical cancer as well as endometrial cancer patients a single agent therapy in several tumor types [280a]. Panobinostat previously with standard chemotherapy [282b]. 218 is a pan-deacetylase inhibitor and induces death of tumor cell Dolastatin 15 222, a seven-subunit depsipeptide derived from lines but not the normal cells [280b]. Panobinostat 218 is currently in Dolabella auricularia, is a potent antimitotic agent structurally Phase Ib/II clinical trils as monotherapy and in combination with related to the antitubulin agent dolastatin 10 224,afive-subunit chemotherapy and/or targeted therapy against Hodgkins peptide obtained from the same organism [283]. Although first lymphoma, MM, AML/MDS and other hematological malignancies isolated from a sea hare D. auricularia, the dolastatins (222 & 224) while global enrollment for Phase III trial in relapsed MM is have cynobacteria origin. Tasidotin (synthadotin, ILX-651, 223), underway. a third-generation analog of 222 that induces G2/M phase cell cycle Bryostatin 1 219, a macrolide lactone first isolated from extracts arrest by inhibiting tubulin polymerization in vitro similar to the of a species of bryozoan, Bugula neritina collected in the Gulf of vinca alkaloids [284a], was evaluated by Genzyme in Phase I/II trials California and Mexico, exerts antineoplastic activity by inhibiting against solid tumors [284b]. In May 2009, Genzyme signed an PKC [281a]. Bryostatin 1 219 has orphan drug status granted by the agreement with Ergomed for the co-development of 223 as an B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807 4799 antineoplastic agent. Soblidotin (YHI-501, TZT-1027, auristatin PE, against severe psoriasis. Various other Phase II clinical trials for 226 225), a derivative of 224 that inhibits tubulin polymerization, in melanoma, NSCLC and hepatocarcinoma are still running. In June resulting in G2/M phase cell cycle arrest and apoptosis, [284c] is 2009, PharmaMar licensed 226 to Medimetriks Pharmaceuticals for Ò under Phase II clinical development by Yakult Honsha for treatment uses other than oncology and neurology [285b]. PM02734 (Irvalec , of solid tumors. 227) is another derivative of 226 being evaluated in Phase II Kahalalide F 226, a depsipeptide that alters lysosomal development by PharmaMar against solid tumors. As on February membrane function was originally extracted from the Hawaiian sea 2010, PharmaMar are recruiting for a Phase I study of 226 as slug Elysia rufescens [285a]. Kahalalide F 226 alters lysosomal combination therapy with erlotinib against advanced malignant membrane function, and as of October 2008 it is in Phase II trials solid tumors.

OCH3

H3C CH3 N O O O N O NH H3C O CH3 O CH3 O O N H3C O OH N N O H H3C NH O O H3C O CH3 CH H C 3 3 CH3 CH3 212 CH3 CH3 H H H H H O O O H H O O O O O O O HO H H H H H CH2 O O O H H CH CH O 3 3 O OH HO O H C 3 O H H 213 O H2C CH3 HO H H3C CH3 O O O CH3 O O H3C CH3 H H N CO2H NH CH2 N 2 O O H CH O HN O CH 3 O N 3 CH3 H3C CH3 H C 3 215 O OH Br

H2C 214 OH OH CH O N H C CH 3 H 3 3H3C CH3 S N O CH3 N S Br H N N CO2H N 217 O N HO H H3C OAc O CH3 H3C H3C CH3 HO O O 216 O OH N O O H H N O HO OCH3 HO O OH HN H3C H3C CH3 218 CH3 OCH3 219 O O O H3C 4800 B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807 B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807 4801

Ò 8.2. NPeantibody anticancer conjugates (Mylotarg ) 228, a humanized anti-CD33 antibody linked to cal- icheamicin 229 [286b,c], a cytotoxin enediyne antibiotic derived During the last few decades, conjugation of potent anticancer from the bacteria Micromonospora echinospora, was the first and agents to various supports such as antibodies, polymers, liposomes only approved antibody-anticancer conjugate co-developed by and nanoparticles for anticancer drug delivery has been extensively Wyeth and UCB Pharma. explored, hoping to improve the efficacy and to reduce side effects Another calicheamicin-antibody conjugate, inotuzumab ozoga- of chemotherapy. Certain kind of anticancer drug nanovectors have micin (CMC-544) having the same CalichDMH and hydrazone been developed to target tumors [286a]. Zinostatin stimalamer linker attached to humanized IgG4 anti-CD22 [287], is being (ZSS), synthesized by conjugation of one molecule of neo- developed by Wyeth and UCB Pharma. CD22 is a B-lymphoid carzinostatin (NCS) chromoprotein and two molecules of lineage-specific differentiation antigen that undergoes rapid poly(styrene-co-maleic acid), was first polymer-based anticancer internalization upon binding and delivers the conjugated Cal- agent launched by Yamanouchi (now Astellas) in Japan for the ichDMH inside the cancer cells. Inotuzumab ozogamicin is under treatment of hepatocellular carcinoma. Gemtuzumab ozogamicin Phase II/III trials against non-Hodgkin’s lymphoma as combination 4802 B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807

therapy with rituximab, a chimeric human IgG1 antibody that positive Phase I/II trials in the 1970s, failed to show significant targets another B-lymphoid lineage-specific molecule, CD20. efficacy at non-toxic concentrations. Maytansine 230, a macrolide isolated from plants of the genus To exploit the anticancer potential of these compounds Immu- Maytenus, inhibits the assembly of microtubules by binding to noGen introduced new maytansinoid-antibody conjugates [288], tubulin at the rhizoxin binding site. Maytansine 230 despite e.g., IMGN-242 (HuC242-DM4, 231), a conjugate of the cytotoxic

Table 2 Halted or discontinued NP’s in oncology [16].

Lead and source Name (synonym) Mechanism of action Comment Plant Camptothecin 133 Rubitecan (OrathecinÔ, 9-NC) Topoisomerase I SuperGen discontinued development Paclitaxel 148 BMS-184476 Tubulin stabilization No update by BMS BMS-275183 Tubulin stabilization Phase II trials halted by BMS TL-310 Tubulin stabilization Not on clinicaltrials.gov Simotaxel(MST-997, TL-909) Tubulin stabilization Phase I trials terminated (Wyeth/Taxolog) Vinblastine 146 (HydravinÔ, KRX-0403) Tubulin binding Keryx discontinued Microorganism Doxorubicin 183 Galarubicin (DA-125) Topoisomerase II inhibition Not listed on Dong A pipeline Spicamycin KRN-5500 89 DNA synthesis inhibitor Discontinued by Kirin Brewery Rebeccamycin (staurosporine 196) Edotecarin (J-107088) Topoisomerase I Discontinued in 2005 by Pfizer XL-119, NSC 655649, BMY-27557 Topoisomerase II Helsinn Healthcare discontinued Epothilone D 206 KOS-862 207 Tubulin stabilization Discontinued by Kosan and Roche Patupilone 21 ABJ879 Tubulin stabilization Not in Novartis’s pipeline BMS-310705 Tubulin stabilization Not listed in BMS’s pipeline Fumagillin 3 CKD-732 MetAP2 inhibition No update by Chong Kun Dang PPI-2458 MetAP2 inhibition GSK terminated the trial Marine Hemiasterlin 215 HTI-286 (SPA-110) Tubulin assembly inhibition Discontinued by Wyeth in 2005 Squalamine 118 Squalamine 118 NHE-5 inhibition Trials discontinued by Genaera Dolastatin 10 224 Dolastatin-10 224 Tubulin assembly inhibition Discontinued by NIH B.B. Mishra, V.K. Tiwari / European Journal of Medicinal Chemistry 46 (2011) 4769e4807 4803 maytansinoid DM4 and the monoclonal antibody huC242 through [24] (a) Shionogi & Co Ltd.: Press release 9 June 2006. Available at: http://www. a disulfide linker, was developed and evaluated by ImmunoGen as shionogi.co.jp. (b) FDA: Press release 17 October 2007. Available at: http://www.fda.gov. a targeted therapy in Phase II trials for CanAg-expressing cancers, [25] C.M. Slover, K.A. Rodvold, L.H. Danziger, Ann. Pharmacother. 41 (2007) including gastric cancer. In June 2009, ImmunoGen discontinued 965e972. further internal development of 231 and shifted it to out-licensing [26] (a) J. Breedt, J. Teras, J. Gardovskis, et al., Antimicrob. Agents Chemother. 49 (2005) 4658e4666; portfolio. ImmunoGen are also evaluating IMGN-901 (HuN901- (b) N. Kasbekar, Am. J. Health-Syst Pharm. 63 (2006) 1235e1243. DM1, 232), a conjugate of maytansinoid DM1 and huN901 that [27] J.G. McGivern, Neuropsychiatr Dis. 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