Results in Chemistry of Natural Organic Compounds. Synthesis of New Anticancer Vinca Alkaloids and Flavone Alkaloids

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Review Results in Chemistry of Natural Organic Compounds. Synthesis of New Anticancer Vinca Alkaloids and Flavone Alkaloids

Szabolcs Mayer, András Keglevich, Csilla Sepsey Für, Hedvig Bölcskei, Viktor Ilkei, Péter Keglevich * and László Hazai Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, 1111 Budapest, Hungary; [email protected] (S.M.); [email protected] (A.K.); [email protected] (C.S.F.); [email protected] (H.B.); [email protected] (V.I.); [email protected] (L.H.) * Correspondence: [email protected]

Received: 1 July 2020; Accepted: 31 July 2020; Published: 10 August 2020

Abstract: The antitumor indole–indoline alkaloids of the evergreen Catharanthus roseus—namely vinblastine and vincristine—are widely used in chemotherapy of cancer. Many efforts were made to synthesize more efficient derivatives with less side-effect. The 14,15-cyclopropane derivative of vinblastine was synthesized successfully by a five-step procedure starting from vindoline. Vincristine, vinorelbine and several derivatives condensed with a cyclopropane ring were synthesized. Various hybrid molecules were prepared by the coupling reaction of vindoline and methyl ester of tryptophan, which were conjugated by carrier peptides of octaarginine. Studying the halogenation reactions of vindoline and catharanthine some fluorine derivatives were obtained which showed promising antitumor activity on various tumor types. The synthesis of the Aspidospermane alkaloid bannucine and 50-epibannucine were carried out using N-acyliminium intermediates. The same intermediate was also applied in the first synthesis of sessiline. The research group have synthesized of flavonoid alkaloids: dracocephins A and B. Further three flavonoid alkaloids, namely 8-(2”-pyrrolidinon-5 -yl)quercetin, 6-(2 -pyrrolidinon-5 -yl)-( )- 00 00 00 − and 8-(2 -pyrrolidinon-5 -yl)-( )-epicatechin were prepared by acid-catalyzed regioselective Mannich 00 00 − reaction starting from the corresponding flavonoid precursor. Vindoline was also coupled to synthetic pharmacophores, such as triphenylphosphine and various N-heterocycles. Some of these hybrid molecules showed significant antitumor activity. Furthermore, 7-OH and 7-NH modified flavonoid derivatives were synthesized by a regioselective alkylation followed by Smiles rearrangement and hydrolysis.

Keywords: Vinca alkaloids; cyclopropane condensed derivatives; hybrid molecules; N-acyliminium; ﬂavone alkaloids

1. Introduction, Therapy and Previous Results Studies dealing with natural organic compounds of biologic activity can be divided into four main groups: (i) the first is the isolation of the molecule in question from the given plant, (ii) the investigation of the biosynthetic pathways, (iii) elaboration of the total synthesis for preparing the biologic effective structure and (iv) synthesis of new derivatives by modification of the original structure for obtaining more efficient, more selective and less toxic molecules. ( )-Vindoline (1) and (+)-catharanthine (2) are Vinca alkaloids containing an indole skeleton, coupled − together forming the dimer alkaloids (+)-vinblastine (3) and (+)-vincristine (4). Vincristine (4) differs from vinblastine (3) in position 1; vincristine (4) contains on the indole nitrogen atom a formyl group (Figure1) instead of a methyl group as is in the vinblastine ( 3). These compounds can be classified as Vinca alkaloids, which were isolated first in the 1950s from the periwinkle Catharanthus roseus being native

Chemistry 2020, 2, 714–726; doi:10.3390/chemistry2030046 www.mdpi.com/journal/chemistry Chemistry 2020, 2, x 2 formyl group (Figure 1) instead of a methyl group as is in the vinblastine (3). These compounds can be classified as Vinca alkaloids, which were isolated first in the 1950s from the periwinkle Catharanthus roseus being native to Madagascar. These compounds are antitumor agents and are used in anticancer therapy. During cell division they act as inhibitors of tubulin polymerization thus blocking the formation of mitotic spindle. In the cancer cells they also inhibit the DNS repairing mechanism and the synthesis of RNS, inhibiting the DNS-dependent RNS polymerase. In anticancer therapy, these types of compounds are used especially against leukemia and lymphoma.

Chemistry 2020, 2, x 2 Chemistry 2020, 2 715 formyl group (Figure 1) instead of a methyl group as is in the vinblastine (3). These compounds can be classified as Vinca alkaloids, which were isolated first in the 1950s from the periwinkle Catharanthus toroseus Madagascar. being native These to Madagascar. compounds are These antitumor compounds agents ar ande antitumor are used agents in anticancer and are therapy. used in Duringanticancer cell divisiontherapy. theyDuring act ascell inhibitors division of they tubulin act polymerizationas inhibitors of thus tubulin blocking polymeriza the formationtion thus of mitotic blocking spindle. the Information the cancer of cellsmitotic they spindle. also inhibit In the the cancer DNS repairing cells they mechanism also inhibit and the the DNS synthesis repairing of RNS, mechanism inhibiting and the DNS-dependentthe synthesis of RNSRNS, polymerase.inhibiting the In DNS-dependent anticancer therapy, RNS these polymerase. types of compounds In anticancer are usedtherapy, especially these againsttypes of leukemia compounds and are lymphoma. used especially against leukemia and lymphoma.

Figure 1. (1–4) Structure of the most important natural Vinca alkaloids.

In the literature, there are many publication in connection of chemical and biologic feature of vinblastine (3) and vincristine (4) as well as synthesis of their new derivatives having important biologic activity [1–3]. Moreover, in the course of our research work, the purpose was not only the synthesis of new vinblastine (3) and vincristine (4) derivatives, but also the extensive investigation of the chemistry of their monomersFigure vindoline 1. ((11––4)) Structure Structure ( 1of ) the and most important catharanthine natural Vinca alkaloids. (2 ). In 2015, a detailed review was published presenting the most important results obtained by our research group in this area [4]. In the literature, there are manymany publicationpublication in connection of chemical and biologic feature of Flavonoids are secondaryvinblastine ( 3) and vincristineplant (4metabolites) as well asas synthesissynthesis ofofcontaining theirtheir newnew derivativesderivatives numerous having important low-molecular-weight biologic activity [1–3]. [1–3]. Moreover, Moreover, in the course of our research work, the purpose was not only the members [5,6]. Their generalsynthesis of new struct vinblastine ure (3 ) consistsand vincristine of (4) derivatives, a 15-carbon but also the skeletextensive investigation on with of a heterocyclic (pyran) the chemistry of their monomers vindoline (1) and catharanthine (2). In 2015, a detailed review was ring (C) between two phenylpublished presenting rings the(Athe most and importantimportant B) (Figure resultsresults obtainedobtained 2). bybyFlavonoids ourour researchresearch groupgroup have inin thisthis areaarea a broad-spectrum [[4].4]. of biologic Flavonoids are secondary plant metabolitesmetabolites containingcontaining numerousnumerous low-molecular-weightlow-molecular-weight activity including anti-inflammatorymembers [[5,6].5,6]. TheirTheir generalgeneral [7,8], structure structure consistsantivi consists of of aral 15-carbona 15-carbon [8–10], skeleton skelet antioxidant withon with a heterocyclic a heterocyclic (pyran) [11,12] (pyran) ring and antitumor [5,8] effects. Flavonoids have(C)ring between (C)been between two found two phenyl phenyl rings to rings (Abe and(A andable B) B) (Figure (Figure to2 ).dock 2). Flavonoids Flavonoids into have have ATP a a broad-spectrum broad-spectrum binding of of biologic biologic sites using the adenosine activity including anti-inﬂammatoryanti-inflammatory [7,8], [7,8], antivi antiviralral [8–10], [8–10], antioxidant [11,12] [11,12] and antitumor [[5,8]5,8] like part at position 4 andeeffects.ﬀects. 5 Flavonoids [13]. havehave beenbeen found found to to be be able able to to dock dock into into ATP ATP binding binding sites sites using using the adenosinethe adenosine like partlike part at position at position 4 and 4 5and [13 5]. [13].

Figure 2. Basic structure of flavonoids.

2. Research on Vinca Alkaloids

2.1. Derivatives Condensed the Three-Membered Rings Figure 2. Basic structure of ﬂavonoids. Figure 2. Basic structure of flavonoids.

2. Research on Vinca Alkaloids

2.1. Derivatives Condensed the Three-Membered Rings

Chemistry 2020, 2 716

2. Research on Vinca Alkaloids

2.1. Derivatives Condensed the Three-Membered Rings It was observed recently that the saturation of the carbon–carbon double bond in position 14,15 of vinblastine (3) by catalytic hydrogenation decreased the biologic effect almost with two orders of magnitude [14]. Considering the drastic change in the biologic activity of this rather large molecule was caused by a minor structural modification; it can be concluded that this C=C double bond has an important role in the biologic effect. Since that, these compounds can be seen appropriate for cyclopropanation, the question is coming up, how the biologic activities change in the case of replacing this double bond with cyclopropane ring having a similar electron structure. This was the reason to propose the synthesis of new vinblastine derivatives condensed with cyclopropane ring in position 14,15. Cyclopropane skeletons can be found in several molecules—as well as in natural organic compounds in a condensed form or as substituents [15]. Nevertheless, the cyclopropane ring has specific properties thanks to its unique structure. Based on the NMR spectra of the different cyclopropane derivatives, it can be concluded that the C–H bond in the cyclopropane ring has larger s-character than in other hydrocarbons. This is the reason, however, that the C–C bonds have larger p-character. It was calculated that the s-character of these C–C bonds is not more than 17%, so that it corresponds to the special sp5 hybrid state. This is supported by the C–C coupling constants measured in the 13C-NMR spectra of cyclopropane derivatives [16]. The 1H-NMR shifts of some cyclopropane derivatives are also interesting [17,18]. It can be observed that the chemical shift is slightly increased in the case of the possibility of conjugation, however, development of an aromatic character causes an enormous increase in the chemical shift, e.g., the value of cyclopentadiene-spiro-cyclopropane changes almost fourfold compared to the saturated cyclopentane-spiro- cyclopropane. Thus, one of cyclopropane ring can give two electrons to form the aromatic delocalized electron sextet. X-ray crystallographic investigations confirmed that the C–C bonds in cyclopropane are shorter than usual in the normally saturated analogs and show slight diffraction because of the large strain of the cyclopropane ring [19]. Therefore, the classical valence theories in the case of cyclopropane can be hardly used. Moreover, how it changes the biologic activity? Many methods can be offered for the preparation of cyclopropane derivatives. Of these, the classic Simmons–Smith reaction exceeds, in which the carbene unit is given by diethyl zinc [20]. At first, the direct cyclopropanation of vinblastine (3) was tried. However, it failed using known procedures. Then the monomer vindoline (1) was treated with diethylzinc and diiodomethane, protecting the position 10 of vindoline (1) with a bromine substituent for avoiding the dimerization reaction taking place through the diiodomethane. Hence, thus, we succeeded in the synthesis of the desired 14,15-cyclopropanovinblastine (10) in an indirect way by a 5-step synthesis [4,21–23]. In the first step vindoline (1) was brominated by N-bromosuccinimide in the position 10 (Figure3) then in the second reaction step, the cyclopropane ring was formed into the position 14,15. Following the bromo atom was hydrogenated from C-10 by sodium borohydride in the presence of a palladium catalyst on charcoal. Then the obtained 14,15-cyclopropanovindoline (8) was coupled with catharanthine (2) resulting in the 14,15-cyclopropanoanhydrovinblastine (9)[21,24]. The last step was the hydration of the 150-200 carbon–carbon double bond obtaining the 14,15-cyclopropanovinblastine (10). The 14,15-cyclopropanovincristine (11) was prepared by the CrO3 oxidation of cyclopropane derivative (10) of vinblastine (3)[21,25]. On the base of our results, further dimer alkaloids condensed with cyclopropane ring were synthesized [22]. The cyclopropane derivative (12) of vinorelbine was obtained from the ring contraction reaction of 14,15-cyclopropanoanhydrovinblastine (9) (Figure4). Chemistry 2020, 2, x 4

Chemistry 2020, 2 717 Chemistry 2020, 2, x 4

Figure 3. Synthesis of (10) 14,15-cyclopropanovinblastine and (11) 14,15-cyclopropanovincristine.

On the base of our results, further dimer alkaloids condensed with cyclopropane ring were synthesized [22]. The cyclopropane derivative (12) of vinorelbine was obtained from the ring contraction reaction of 14,15-cyclopropanoanhydrovinblastine (9) (Figure 4). Figure 3. Synthesis of (10) 14,15-cyclopropanovinblastine and (11) 14,15-cyclopropanovincristine. Figure 3. Synthesis of (10) 14,15-cyclopropanovinblastine and (11) 14,15-cyclopropanovincristine.

Figure 4. Synthesized semisynthetic Vinca alkaloids condensed with a cyclopropane ring. (12) 14,15- cyclopropanovinorelbineFigure 4. Synthesized semisynthetic and (13–14) twoVinca other alkaloids derivatives condensed of 12 with. a cyclopropane ring. (12) 14,15- cyclopropanovinorelbine and (13–14) two other derivatives of 12. Synthesis of 14,15-cyclopropanovinorelbine (12) gave the possibility to prepare two further cyclopropanovinorelbine derivatives, the 1-N-formyl-14,15-cyclopropanovinorelbine (13) and the 50-demethylene–vinblastine cyclopropane derivative (14). The 13 N-formyl derivative was obtained by CrO3 oxidationFigure 4. Synthesized reaction of semisynthetic cyclopropanovinorelbine Vinca alkaloids condensed (12), compound with a cyclopropane14 was formed ring.by (12 the) 14,15- hydration of the 15cyclopropanovinorelbine0-200 carbon–carbon doubleand (13–14 bond) two also other of derivatives12. of 12.

Chemistry 2020, 2 718

Dimer alkaloids condensed with a cyclopropane ring synthesized by us were investigated by the National Institute of Health (NIH, Bethesda, MD, USA) on 60 different cell lines of 9 different tumor types. The cytostatic activity of compounds 14,15-cyclopropanovinblastine (10) and 14,15-cyclopropanovincristine (11)slightlydiffersfromvinblastine(3)andvincristine(4)usedintherapyasanticancermedicines; thecyclopropane analogs are more effective inhibitors for the cell proliferation, respectively and destroy the tumorous cells with more efficiency. The 14,15-cyclopropanovinblastine (10) shows excellent anticancer activity in the case of leukemia, non-small cell lung cancer,colon cancer,melanoma and breast cancer,the vincristine derivative (11) is outstanding against colon cancer, melanoma, ovarian cancer and prostate cancer. From the vinorelbine derivatives, the 14,15-cyclopropanovinorelbine (12) has the most significant effect in the case of non-small cell lung cancer, colon cancer, central nervous system cancers, melanoma and breast cancer. The 1-N-formyl-14,15-cyclopropanovinorelbine (13) shows an important activity and significant selectivity on COLO-205 colon cancer cell line [23].

2.2. Vinca Hybrid Molecules Containing Amino Acid Esters In the last few years, there was great interest in the hybrid molecules. Among anticancer compounds, some hybrid molecules were built by coupling an antiproliferative structural part with another pharmacophore. From our compounds at first vindoline (1) was coupled with amino acid esters [26]. 10-bromovindoline (6) was treated with hydrazine resulting in 15a hydrazide derivative and the latter was coupled with (l)- and (d)-tryptophan methyl ester, respectively, by means of azide coupling method known in peptide chemistry (Figure5). Di ﬀerent derivatives of vindoline (1) were used: 14,15-dihydro-, 14,15-cyclopropanovindoline, moreover, the derivatives not containing a bromo substituent at position 10 were also synthesized. The cytostatic activity of the prepared compounds (17a–l) was investigated on HL-60 leukemia cells. It was established, that the most eﬀective molecule was compound 17f, which has hydrogen atom at C–10 and is coupled with (l)-tryptophan methyl ester at position 16. Derivatives of vinblastine (3) coupled also with (l)-tryptophan methyl ester, conjugated with N-terminal of octaarginine carrier peptide after hydrolysis of the ester to the corresponding carboxylic acid showed substantially larger activity [27].

2.3. Vinca Hybrid Molecules Containing Steroid Vectors The conjugation of Vinca alkaloids with (l)- and (d)-tryptophan methyl ester proved that the cytotoxic effect of vindoline (1) can be promoted by coupling this monomer with suitable pharmacophores. As a continuation of our work we aimed to synthesize vindoline (1) steroid hybrids presuming that the lipophilic steroid vector can facilitate Vinca alkaloids to pass through the cell membranes and reach higher bioavailability. Accordingly, 5α-dihydrotestosterone and 19-nortestosterone were connected to vindoline (1) in positions 10 and 17 through succinate linkers. From the successfully synthesized four new hybrid derivatives, the most efficient one was compound 18, where 19-nortestosterone was coupled with vindoline (1) in position 17 (Figure6) [ 28]. According to the in vitro biologic evaluations of NIH (USA), compound 18 displayed increased cell growth inhibition than vindoline (1), furthermore, it showed a higher antitumor effect on several cell lines even than vinblastine (3) sulfate used in therapy.

2.4. Vinca Hybrid Molecules Containing Synthetic Pharmacophores After the encouraging results derived from the conjugation of natural pharmacophores (amino acid esters and steroids) and Vinca alkaloids, our next research project was to combine vindoline (1) with well-known synthetic pharmacophores for example triphenylphosphine and certain N-heterocycles such as morpholine, piperazine and N-methylpiperazine. These moieties are widely used pharmacophores in modern drug discovery and proved to be efficient structural units of several drugs on market [29,30]. Our main purpose was still the same: producing new vindoline hybrid molecules which could have potential anticancer activity. First, vindoline (1) was O-acylated with 4-bromobutyric acid, after hydrolysis Chemistry 2020, 2, x 6

Chemistry 2020, 2 719

in position 17. After this step, the linker-containing vindoline derivative (19) was successfully coupled with Chemistry the2020 mentioned, 2, x synthetic pharmacophores to give the expected hybrid molecules (20–23) (Figure7) [ 31–33]. 6

Figure 5. Synthesis of different vindoline derivatives (17a–l) coupled with (L)- and (D)-tryptophan methyl ester in position 16.

2.3. Vinca Hybrid Molecules Containing Steroid Vectors

The conjugation of Vinca alkaloids with (L)- and (D)-tryptophan methyl ester proved that the cytotoxic effect of vindoline (1) can be promoted by coupling this monomer with suitable pharmacophores. As a continuation of our work we aimed to synthesize vindoline (1) steroid hybrids presuming that the lipophilic steroid vector can facilitate Vinca alkaloids to pass through the cell membranes and reach higher bioavailability. Accordingly, 5α-dihydrotestosterone and 19- nortestosterone were connected to vindoline (1) in positions 10 and 17 through succinate linkers. From the successfully synthesized four new hybrid derivatives, the most efficient one was compound 18, where 19-nortestosterone was coupled with vindoline (1) in position 17 (Figure 6) [28]. According to the in vitro biologic evaluations of NIH (USA), compound 18 displayed increased cell growth inhibition than vindoline (1), furthermore, it showed a higher antitumor effect on several cell lines Figure 5. Synthesis of diﬀerent vindoline derivatives (17a–l) coupled with (l)- and (d)-tryptophan even Figurethan vinblastine 5. Synthesis ( 3of) sulfatedifferent used vindoline in therapy. derivatives (17a–l) coupled with (L)- and (D)-tryptophan methyl ester in position 16. methyl ester in position 16.

2.3. Vinca Hybrid Molecules Containing Steroid Vectors

The conjugation of Vinca alkaloids with (L)- and (D)-tryptophan methyl ester proved that the cytotoxic effect of vindoline (1) can be promoted by coupling this monomer with suitable pharmacophores. As a continuation of our work we aimed to synthesize vindoline (1) steroid hybrids presuming that the lipophilic steroid vector can facilitate Vinca alkaloids to pass through the cell membranes and reach higher bioavailability. Accordingly, 5α-dihydrotestosterone and 19- nortestosterone were connected to vindoline (1) in positions 10 and 17 through succinate linkers. From the successfully synthesized four new hybrid derivatives, the most efficient one was compound 18, whereFigure 19-nortestosterone 6.Figure (18) 17-desacetylvindoline-19-nortestosterone 6. (18) 17-desacetylvindoline-19-nortestosterone was coupled with vindoline hemisuccinate hemi (1succinate) in position hybrid hybrid molecule 17 molecule (Figure found to6)found have [28]. to According have an outstanding antiproliferative activity. to thean inoutstanding vitro biologic antiproliferative evaluations activity. of NIH (USA), compound 18 displayed increased cell growth inhibition than vindoline (1), furthermore, it showed a higher antitumor effect on several cell lines even than vinblastine (3) sulfate used in therapy.

Figure 6. (18) 17-desacetylvindoline-19-nortestosterone hemisuccinate hybrid molecule found to have an outstanding antiproliferative activity.

Chemistry 2020, 2, x 7

2.4. Vinca Hybrid Molecules Containing Synthetic Pharmacophores After the encouraging results derived from the conjugation of natural pharmacophores (amino acid esters and steroids) and Vinca alkaloids, our next research project was to combine vindoline (1) with well-known synthetic pharmacophores for example triphenylphosphine and certain N- heterocycles such as morpholine, piperazine and N-methylpiperazine. These moieties are widely used pharmacophores in modern drug discovery and proved to be efficient structural units of several drugs on market [29,30]. Our main purpose was still the same: producing new vindoline hybrid molecules which could have potential anticancer activity. First, vindoline (1) was O-acylated with 4- bromobutyric acid, after hydrolysis in position 17. After this step, the linker-containing vindoline derivativeChemistry 2020 (19, 2 ) was successfully coupled with the mentioned synthetic pharmacophores to give the720 expected hybrid molecules (20–23) (Figure 7) [31–33].

17 VIN O O Br

20,80%

triphenylphosphine P

17 O H3CO N O H OH H CH3 COOCH3 N H Br N 19

O H N N morpholine CH3

N N-methylpiperazine H 17 VIN O piperazine 17 O VIN O O 17 17 N O VIN O O VIN O O N N CH3

21,74% N N 23,43%

22,36%

Figure 7.7. ((2020––2323)) SynthesizedSynthesizedVinca Vincaalkaloid alkaloid hybrids hybrids by theby conjugationthe conjugation of (1 )of vindoline (1) vindoline and the and chosen the chosensynthetic synthetic pharmacophores. pharmacophores.

The new compounds ( (2020–23) were were tested tested on on 60 60 different different huma humann tumor tumor cell cell lines lines inin vitro vitro (NIH,(NIH, Bethesda, MD,MD, USA). USA). The The results results showed showed that the th linker,at the the morpholine,linker, the andmorpholine, the N-methylpiperazine and the N- methylpiperazinemoieties could not moieties improve could the anticancer not improve activity the of anticancer vindoline activity (1). However, of vindoline the 20 phosphonium-salt(1). However, the 20and phosphonium-salt the 22-vindoline dimer and the (containing 22-vindoline piperazine) dimer represented(containing outstandingpiperazine) cytotoxicrepresented activities. outstanding These cytotoxicderivatives activities. (20, 22) were These more derivatives potent than (20 vinblastine, 22) were more (3) sulfate potent itself than on severalvinblastine cell lines. (3) sulfate The anticancer itself on severalinvestigation cell lines. (NIH, The USA) anticancer of these compoundsinvestigation (19 (NIH,–23) confirmed USA) of ourthese hypothesis compounds suggesting (19–23 vindoline) confirmed (1) ourcan becomehypothesis an effectivesuggesting anticancer vindoline drug (1 by) can conjugating become an it witheffective suitable anticancer pharmacophores. drug by conjugating it with suitable pharmacophores. 2.5. Halogenation Reactions of VINCA Alkaloids

The mechanism of the cyclopropanation reaction of vinblastine (3) presented in chapter 2.1. was investigated and established the reason for forming the N-methyl quaternary salt of vinblastine instead of cyclopropanation in the course of Simmons–Smith reaction [34]. Halogenation reactions of monomer indole alkaloids vindoline (1) and catharanthine (2) were studied in detail, first of all the introduction of fluorine atom was investigated (Figure8). In both cases the reactions resulted in unexpected products. Thus, in the case of vindoline (1) the fluoro containing quinone derivative (24) was formed and, in the case of catharanthine (2) a fluoro substituted indolenine (25) could be isolated [35]. Chemistry 2020, 2, x 8

2.5. Halogenation Reactions of VINCA Alkaloids Chemistry 2020, 2, x 8 The mechanism of the cyclopropanation reaction of vinblastine (3) presented in chapter 2.1. was investigated2.5. and Halogenation established Reactions the of VINCA reason Alkaloids for forming the N-methyl quaternary salt of vinblastine instead of cyclopropanationThe mechanism of in the the cyclopropanation course of Simmons–Smith reaction of vinblastine reaction (3) presented [34]. in chapter 2.1. was Halogenationinvestigated reactions and established of monomer the reason indole for forming alkaloids the N-methyl vindoline quaternary (1) and salt ofcatharanthine vinblastine (2) were instead of cyclopropanation in the course of Simmons–Smith reaction [34]. studied in detail,Halogenation first of reactionsall the introductionof monomer indole of alkaloidsfluorine vindoline atom was(1) and investigated catharanthine ((Figure2) were 8). In both cases the reactionsstudied in detail,resulted first ofin all unexpected the introduction products. of fluorine Thus,atom was in investigatedthe case of(Figure vindoline 8). In both (1 ) the fluoro containing casesquinone the reactions derivative resulted (in24 unexpected) was formed products. and, Thus, in in the case case of vindolineof catharanthine (1) the fluoro (2) a fluoro Chemistry 2020, 2 721 substitutedcontaining indolenine quinone (25) derivativecould be ( 24isolated) was formed [35]. and, in the case of catharanthine (2) a fluoro substituted indolenine (25) could be isolated [35].

Figure 8. (24–25) Halogenated products obtained in the fluorination reactions of (1) vindoline and Figurecatharanthine 8. (24– 25(2)). Halogenated products obtained in the ﬂuorination reactions of (1) vindoline and – Figure 8. (catharanthine24 25) Halogenated (2). products obtained in the fluorination reactions of (1) vindoline and catharanthine3. Vindoline (2). and Flavone Derivatives Containing 2-Pyrrolidone Ring 3. Vindoline and Flavone Derivatives Containing 2-Pyrrolidone Ring Our other important research area was the chemistry of Aspidospermane alkaloids. A detailed 3. Vindolinereview andOur was otherFlavone published important Derivatives in research 2008 by area us Containing was presenting the chemistry the 2-Pyrrolidone synthesis of Aspidospermane and derivatives Ringalkaloids. of A detailedthese types review of wasalkaloids published [36]. Then in 2008 the by firs ust synthesis presenting of thebannucine synthesis (26 and) and derivatives 5′-epibannucine of these (27 types) was of elaborated alkaloids [37]. [36]. Our otherThenThis alkaloid the important first synthesiswas first research isolated of bannucine in area 1986 (26 fromwas) and the 5the0 -epibannucineleaves chemistry of Catharanthus (27 of) was Aspidospermane roseus elaborated by Atta-Ur-Rahman [37]. This alkaloids. alkaloid and A detailed review waswascoworkers published first isolated [38]. Bannucine inin 1986 2008 from ( 26by the) is leavesusa derivative presenting of Catharanthus of vindoline the roseus synthesis(1)by having Atta-Ur-Rahman a 2-pyrrolidoneand derivatives and ring coworkers in position of [38these]. types of Bannucine10. The key (26 step) is aof derivative the procedure of vindoline appears (1) the having reaction a 2-pyrrolidone between the ring natural in position (−)-vindoline 10. The key (1) step and of a alkaloids [36].thecyclic procedure Then N-acyliminium the appears first intermediate.synthesis the reaction betweenof As bannucine a result the naturalof the (26 reaction ( ) )-vindolineand not5′-epibannucine only (1) the and bannucine a cyclic N(27-acyliminium (26) ),was but alsoelaborated [37]. − This alkaloidintermediate.its 5was′-epimeric first As isomerisolated a result (27 of )in thewas 1986 reaction formed from not in onlyanthe approximate theleaves bannucine of ratioCatharanthus (26 ),of but 2:3 also(Figure its roseus 5 09).-epimeric The by isomers Atta-Ur-Rahman isomer were (27) and coworkerswas separated,[38]. formed Bannucine and in an their approximate structure(26) is ratioa was derivative of identified 2:3 (Figure ofalso9). vindoline Theby X-ray isomers crystallography. ( were1) having separated, a The and2-pyrrolidone pure their structureepimers were was ring in position identifiedinvestigated also on by 57 X-ray cell crystallography.lines of different The types pure of epimerscancer, however, were investigated important on anticancer 57 cell lines activity of different was 10. The keytypesnot step found of cancer,of [36]. the however, procedure important appears anticancer the activity reaction was not between found [36 ].the natural (−)-vindoline (1) and a cyclic N-acyliminium intermediate. As a result of the reaction not only the bannucine (26), but also its 5′-epimeric isomer (27) was formed in an approximate ratio of 2:3 (Figure 9). The isomers were separated, and their structure was identified also by X-ray crystallography. The pure epimers were investigated on 57 cell lines of different types of cancer, however, important anticancer activity was not found [36].

FigureFigure 9. 9.( 26(26)) Synthesis Synthesis of of bannucine bannucine andand ((2727)) itsits epimerepimer 50′-epibannucine-epibannucine with with different diﬀerent methods. methods.

TheThe firstfirst synthesissynthesis of of sessiline sessiline ( 30(30) was) was achieved achieved by by applying applying the the experiences experiences gained gained in thein the field field of acylaminocarbinolsof acylaminocarbinols [39]. [39]. The alkaloidThe alkaloid sessiline sessiline (30) was (30 isolated) was isolated from the from fruits the of Acanthopanas fruits of Acanthopanas sessiliflorus insessiliflorus 2002 [40]. in The 2002 molecule [40]. The consists molecule of two consists 5-membered of two heterocycles 5-membered coupling heterocycles through coupling an acylaminocarbinol through an ether-typeacylaminocarbinol bond (Figure ether-type 10). Sessiline bond (30 )(Figure was prepared 10). Sessiline by reaction (30 of) 5-hydroxypyrrolidin-2-onewas prepared by reaction (28 )of with 5- Chemistry 20205-hydroxymethyl-furfuralhydroxypyrrolidin-2-one, 2, x ((2928)) at with 60 ◦ C5-hydroxymethyl-furfural with 54% yield [39]. (29) at 60 °C with 54% yield [39]. 9

Figure 9. (26) Synthesis of bannucine and (27) its epimer 5′-epibannucine with different methods.

Figure 10. An alternative method to synthesize (30) sessiline from (28) 5-hydroxypyrrolidin-2-one and TheFigure first 10. synthesis An alternative of sessiline method to(30 synthesize) was achieved (30) sessiline by applyingfrom (28) 5-hydroxypyrrolidin-2-one the experiences gained and in the field (29) 5-hydroxymethyl-furfural. of acylaminocarbinols(29) 5-hydroxymethyl-furfural. [39]. The alkaloid sessiline (30) was isolated from the fruits of Acanthopanas sessiliflorus in 2002 [40]. The molecule consists of two 5-membered heterocycles coupling through an acylaminocarbinolPreviously in ourether-type department, bond serious (Figure research 10). waSessilines followed (30 on) thewas flavonoid prepared chemistry. by reaction On the of 5- hydroxypyrrolidin-2-onebase of these results, the ( 28synthesis) with 5-hydroxymethyl-furfural of flavones coupled with a (heterocyclic29) at 60 °C ringwith was 54% investigated. yield [39]. dracocephin A (32) and its regioisomer B (33) as a mixture of four stereoisomers were isolated in China from Dracocephalum rupestre in 2008 by Ren and coworkers [41]. A mixture of dracocephin A (32) and B (33) in a ratio of 43:57 was prepared in a one-step reaction from (±)-naringenin (31) and separated by analytical chiral HPLC, the absolute configuration was identified by HPLC–ECD measurements and by using TDDFT–ECD (Time-dependent density functional theory electronic circular dichroism) calculations (Figure 11). The physicochemical parameters and biologic activities of the compounds were also studied.

Figure 11. Synthesis of dracocephin (32) A and (33) B.

Further flavone alkaloids were also synthesized: 8-(2′′-pyrrolidinon-5′′-il)-quercetin (35) and (−)- epicatechin (37) with the same substituent in position eight (38) and in position six (39), respectively [42,43]. Starting from quercetin (34) compound 35 and its C-6 (36) isomer were obtained in a ratio of 94:6 (Figure 12). By a similar procedure, epicatechin (37) yielded a mixture of 38 and 39 in a 87:13 ratio (Figure 13). These derivatives were prepared by acid-catalyzed regioselective Mannich reaction in which the in situ generated N-acyliminium ion started an electrophile attack to the aromatic A ring of the corresponding flavonoid precursors.

Chemistry 2020, 2, x 9

ChemistryFigure2020 ,10.2 An alternative method to synthesize (30) sessiline from (28) 5-hydroxypyrrolidin-2-one and 722 (29) 5-hydroxymethyl-furfural.

PreviouslyPreviously in in ourour department,department, seriousserious researchresearch was was followed followed on onthe the flavonoidflavonoidchemistry. chemistry. On Onthe the basebase ofof thesethese results,results, thethe synthesissynthesis ofof flavonesflavones coupledcoupled withwith aa heterocyclicheterocyclic ringring waswas investigated.investigated. dracocephindracocephin A A (32 (32) and) and its its regioisomer regioisomer B ( 33B )(33 as) a as mixture a mixture of four of stereoisomersfour stereoisomers were isolatedwere isolated in China in fromChinaDracocephalum from Dracocephalum rupestre rupestrein 2008 byin 2008 Ren andby Ren coworkers and coworkers [41]. A mixture [41]. A ofmixture dracocephin of dracocephin A (32) and A B((3233) )and in a B ratio (33) ofin 43:57a ratio was of prepared43:57 was in prepared a one-step in reactiona one-step from reaction ( )-naringenin from (±)-naringenin (31) and separated (31) and ± byseparated analytical by chiral analytical HPLC, chiral the absolute HPLC, configurationthe absolute wasconfiguration identified was by HPLC–ECD identified by measurements HPLC–ECD andmeasurements by using TDDFT–ECD and by using (Time-dependent TDDFT–ECD density(Time-depe functionalndent density theory electronic functional circular theory dichroism) electronic calculationscircular dichroism) (Figure calculations11). The physicochemical (Figure 11). The parameters physicochemical and biologic parameters activities and of biologic the compounds activities wereof the also compounds studied. were also studied.

FigureFigure 11.11.Synthesis Synthesis ofof dracocephindracocephin ((3232)) A A and and ( 33(33)) B. B.

FurtherFurther ﬂavoneflavone alkaloids were also also synthesized: synthesized: 8-(2 8-(2′′-pyrrolidinon-500-pyrrolidinon-5′′-il)-quercetin00-il)-quercetin (35 ()35 and) and (−)- (epicatechin)-epicatechin (37) (with37) with the same the samesubstituent substituent in position in position eight (38 eight) and in (38 position) and in six position (39), respectively six (39), − respectively[42,43]. Starting [42,43 from]. Starting quercetin from (34 quercetin) compound (34) 35 compound and its C-635 (and36) isomer its C-6 (were36) isomer obtained were in obtaineda ratio of in94:6 a ratio (Figure of 94:6 12). (Figure By a similar 12). By procedure, a similar procedure, epicatechin epicatechin (37) yielded (37) a yielded mixture a mixtureof 38 and of 3938 andin a 3987:13in aratio 87:13 (Figure ratio (Figure 13). These 13). derivatives These derivatives were prepared were prepared by acid-catalyzed by acid-catalyzed regioselective regioselective Mannich Mannich reaction reactionin which in the which in situ the generated in situ generated N-acyliminiumN-acyliminium ion started ion startedan electrophile an electrophile attack to attack the aromatic to the aromatic A ring AChemistryof ring the ofcorresponding 2020 the, 2 corresponding, x flavonoid ﬂavonoid precursors. precursors. 10

Figure 12. Synthesis of compound 35 and its (36) C-6 isomer from (34) quercetin.. Figure 12. Synthesis of compound 35 and its (36) C-6 isomer from (34) quercetin.

Figure 13. Synthesis of compound 38 and 39 from (37) epicatechin by an acid-catalyzed regioselective Mannich reaction.

4. 7-OH and 7-NH Modified Flavonoid Derivatives Chrysin (40)—also known as 5,7-dihydroxyflavone—can be found among others in Passiflora caerulea [44,45], honey and propolis. Like several flavonoids, it has a number of biologic effects, of which it is important to mention its anticancer activity both as a chemopreventive and as a chemotherapeutic agent [46]. The driving force of our work was that several 7-O-modified derivatives had been found to be effective against different malignant tumor cells [47,48]. Therefore, we synthesized several new aryloxy acetamide derivatives (45–48) (Figure 13). These products were rearranged to a biphenyl amine structure via Smiles rearrangement and hydrolysis to obtain a new series of 7-aminoflavone derivatives (49–52) (Figure 14) [49].

Chemistry 2020, 2, x 10

. Chemistry 2020, 2 723 Figure 12. Synthesis of compound 35 and its (36) C-6 isomer from (34) quercetin.

Figure 13. Synthesis of compound 38 and 39 from (37) epicatechin by an acid-catalyzed regioselective FigureMannich 13. reaction. Synthesis of compound 38 and 39 from (37) epicatechin by an acid-catalyzed regioselective Mannich reaction. 4. 7-OH and 7-NH Modiﬁed Flavonoid Derivatives 4. 7-OH and 7-NH Modified Flavonoid Derivatives Chrysin (40)—also known as 5,7-dihydroxyflavone—can be found among others in Passiflora caerulea [44,45], honeyChrysin and propolis. (40)—also Like known several flavonoids,as 5,7-dihydroxyflavone—can it has a number of biologic be found effects, among of which others it is importantin Passiflora to caeruleamention [44,45], its anticancer honey activity and propolis. both as a chemopreventiveLike several flavonoids, and as a chemotherapeuticit has a number agentof biologic [46]. The effects, driving of whichforce of it our is work important was that to several mention 7-O -modifiedits anticancer derivatives activity had beenboth foundas a tochemopreventive be effective against and different as a chemotherapeuticmalignant tumor cells agent [47, 48[46].]. Therefore, The driving we force synthesized of our work several was new that aryloxy several acetamide 7-O-modified derivatives derivatives (45–48) (Figurehad been 13). found These productsto be effective were rearranged against different to a biphenyl malignant amine structuretumor cells via Smiles [47,48]. rearrangement Therefore, andwe synthesized several new aryloxy acetamide derivatives (45–48) (Figure 13). These products were hydrolysisChemistry to2020 obtain, 2, x a new series of 7-aminoflavone derivatives (49–52) (Figure 14) [49]. 11 rearranged to a biphenyl amine structure via Smiles rearrangement and hydrolysis to obtain a new series of 7-aminoflavone derivatives (49–52) (Figure 14) [49].

FigureFigure 14. 14.Synthesis Synthesis of of 7-OH 7-OH andand 7-NH7-NH modiﬁedmodified flavonoid ﬂavonoid derivatives. derivatives.

TheThe products products (45 (45–52–52) were) were tested tested on on 60 60 didifferentﬀerent human tu tumormor cell cell lines lines inin vitro vitro (NIH,(NIH, MD, MD, USA) USA) andand three three of of the the hydrolyzed hydrolyzed Smiles Smiles products products ((5050––5252)) showedshowed prominent prominent antitumor antitumor effect eﬀect on on several several cellcell lines lines [49 [49].].

AuthorAuthor Contributions: Contributions:S.M., S.M., A.K., A.K., C.S.F., C.S.F., H.B., H.B., V.I.,V.I., P.K.P.K. andand L.H.L.H. wrote the study. study. All All authors authors have have read read and and agreedagreed to theto the published published version version of of the the manuscript. manuscript. Funding:Funding:This This research research received received no no external external funding. funding ConﬂictsConflicts of Interest:of Interest:The The authors authors declare declare no no conﬂict conflicts of of interest. interest.

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