Methods of synthesis of natural indoloquinolines isolated from Cryptolepis sanguinolenta

Nadein, O. N.; Аксенов, Дмитрий А.; Абакаров, Г. М.; Аксенов, Н. А.; Voskressensky, Leonid G.; Aksenov, A. V.

doi:10.1007/s10593-019-02557-8

Cited by 19 publications

(10 citation statements)

References 114 publications

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“…Neocryptolepine (24) has been the focus of several synthetic works previously and multiple reviews are available covering the endeavours. [101,102,176,177] Herein, only the most recent and some notable examples will be discussed.…”

Section: Synthesis Of Neocryptolepine In Recent Literaturementioning

confidence: 99%

Divergent Synthesis of Indolo[3,2- c]quinolines, Neocryptolepines and Related Tetracyclic Ring-Systems Containing Promising Biological Activities

Håheim¹

2022

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Malaria is a devastating tropical disease, claiming approximately 627 000 lives in 2020. Due to the appearance of resistance towards artemisinin-based therapies, the discovery of novel treatments are of paramount importance. The indoloquinoline natural products cryptolepine, neocryptolepine and isocryptolepine, first discovered in the extracts of the African bush plant Cryptolepis sanguinolenta, have been found to exhibit potent antimalarial properties. More- over, several functionalized derivatives of these compounds have shown great promise as an- tiplasmodial agents. The indoloquinoline alkaloids have also been found to possess significant antiproliferative and antimicrobial properties, making them ideal targets for the development into novel drug candidates. The first project in this work details the application of a synthetic approach first devel- oped by Helgeland and Sydnes to assemble various tetracyclic ring systems. The key synthetic strategies being a Suzuki-Miyaura cross-coupling reaction followed by a palladium-catalyzed intramolecular cyclization. Though the approach was unsuitable to construct all the intended target molecules, it furnished the unexpected pyridophenanthridine scaffold. By further inves- tigating alternative protocols for the construction of indoloquinolines, a regiodivergent inter- mediate was discovered, which allowed for the synthesis of both novel pyridophenanthridine and pyridocarbazole scaffolds by utilizing two different reaction protocols. By subjecting this common intermediate to a diazotization-azidation-nitrene insertion approach, the novel pyrido- carbazoles could be furnished in excellent yields. The unexpected formation of a biquinoline bridged by an aniline during a Suzuki-Miyaura cross-coupling reaction, was deemed interesting for development into a transition metal com- plex for catalysis. Through a collaborative effort with Dr. Eugene Khaskin’s group at Oki- nawa Institute of Science and Technology, five quinoline/pyridine N,N,N ligands were designed and synthesized. The key synthetic tools utilized in their construction was either a sequential Suzuki-Miyaura cross-coupling reaction and Buchwald-Hartwig amination or reductive amina- tion. A novel two-step approach for the synthesis of the natural product neocryptolepine from commercially available bromoquinolines was developed. The key transformations being re- gioselective N-alkylations followed by a cascade Suzuki-Miyaura cross-coupling reaction and intramolecular nucleophilic C-N bond formation. The scope and limitations for the novel pro- tocol was evaluated through the preparation of 24 neocryptolepine derivatives, bearing a diverse range of functional groups, where electron-withdrawing group substitutions were generally su- perior. It became apparent that it would also be possible to prepare a library of indolo[3,2-c]quino- lines from the same starting material as the newly devised strategy to produce neocryptolepines. By utilizing a reaction sequence consisting of a Suzuki-Miyaura cross-coupling reaction, in- stallation of an azido moiety and finally photochemical cyclization, this goal was realized, producing a total of 19 indoloquinolines. This protocol was less robost towards substrate func- tionalizations than the neocryptolepine approach, with no apparent trend concerning electron- withdrawing and electron-donating groups being apparent. The photochemical cyclization was hypothesized to proceed via the formation of a reactive singlet nitrene intermediate. Finally, a selection of the prepared tetracyclic compounds assembled during this work was evaluated for their antiplasmodial, antiproliferative and antimicrobial activities by the help of various external collaborators. The most successful compound was revealed to be the novel pyridophenanthridines, displaying more potent antiproliferative activities than doxoru- bicin against human prostate cancer (IC50 = 24 nM). The novel pyridocarbazoles moreover showed excellent inhibition of biofilm formation, with the potential to be developed into a dual anticancer-antimicrobial agent. Of all the tested compounds, only N-methylated pyridocar- bazole was found to contain any significant activity against the evaluated Plasmodium falci- parum strain. The antimicrobial assays revealed the importance of the inclusion of a methyl group for activity, but not strictly in the form of an N-methyl unit, which is the general con- census in the literature thus far. Further, chlorinated indoloquinolines were revealed to contain excellent antimicrobial activity against both Gram-positive and Gram-negative bacterial cell lines.

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Section: Synthesis Of Neocryptolepine In Recent Literaturementioning

confidence: 99%

Divergent Synthesis of Indolo[3,2- c]quinolines, Neocryptolepines and Related Tetracyclic Ring-Systems Containing Promising Biological Activities

Håheim¹

2022

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“…Indolobenzazepines and indoloquinolines are fused heterocyclic scaffolds, which have gained a considerable interest in the field of medicinal chemistry. − Indolo[3,2- d ]benzazepines or paullones (backbone A in Chart ), first synthesized in 1992, were discovered as potential inhibitors of cyclin-dependent kinases (Cdks) ,, with antiproliferative activity similar to that of flavopiridol, the first Cdk-inhibitor that reached clinical trials as an anticancer drug. Later, other possible targets have been identified, namely, sirtuins, , GSK3β, ,,, and mitochondrial malate dehydrogenase .…”

Section: Introductionmentioning

confidence: 99%

Highly Antiproliferative Latonduine and Indolo[2,3-c]quinoline Derivatives: Complex Formation with Copper(II) Markedly Changes the Kinase Inhibitory Profile

et al. 2022

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A series of latonduine and indoloquinoline derivatives HL 1 – HL 8 and their copper(II) complexes ( 1–8 ) were synthesized and comprehensively characterized. The structures of five compounds ( HL 6 , [CuCl(L 1 )(DMF)]·DMF , [CuCl(L 2 )(CH 3 OH)] , [CuCl(L 3 )]·0.5H 2 O , and [CuCl 2 (H 2 L 5 )]Cl·2DMF ) were elucidated by single crystal X-ray diffraction. The copper(II) complexes revealed low micro- to sub-micromolar IC 50 values with promising selectivity toward human colon adenocarcinoma multidrug-resistant Colo320 cancer cells as compared to the doxorubicin-sensitive Colo205 cell line. The lead compounds HL 4 and 4 as well as HL 8 and 8 induced apoptosis efficiently in Colo320 cells. In addition, the copper(II) complexes had higher affinity to DNA than their metal-free ligands. HL 8 showed selective inhibition for the PIM-1 enzyme, while 8 revealed strong inhibition of five other enzymes, i.e., SGK-1, PKA, CaMK-1, GSK3β, and MSK1, from a panel of 50 kinases. Furthermore, molecular modeling of the ligands and complexes showed a good fit to the binding pockets of these targets.

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“…The indoloquinoline framework is found in a variety of natural products and biologically active compounds. − Cryptolepine ( 1 , Figure ) was first isolated from Cryptolepis triangularis, and 2 decades later this alkaloid was also found in the root of the Cryptolepis sanguinolenta, the extract of which has been traditionally used in West Africa to treat malaria, diarrhea, and hypertension . Neocryptolepine ( 2 ) and isocryptolepine ( 3 ) were also isolated from the same plant by several independent research groups. − Isoneocryptolepine ( 4 ) has not yet been isolated from natural sources.…”

Section: Introductionmentioning

confidence: 99%

“…13 In 2014, the Pd-catalyzed arylation of Ugi adducts, obtained from the reaction of indole-2-carboxylic acid, aromatic aldehydes, 2bromoanilines, and isocyanides, for the construction of indoloquinolinone derivatives was developed (Scheme 1b). 14 Using acetyloxy(phenyl)-λ 3 -iodanyl acetate as a hypervalent iodine oxidant in C(sp 2 )−N coupling proved to be an appropriate method for the synthesis of a series of substituted indoloquinolinones from indole-2-carboxylic-acid derivatives with good to excellent yields (Scheme 1c). 15 indoloquinolines (Scheme 1d).…”

Section: ■ Introductionmentioning

confidence: 99%

Synthesis of Indolo[2,3-c]quinolin-6(7H)-ones and Antimalarial Isoneocryptolepine. Computational Study on the Pd-Catalyzed Intramolecular C–H Arylation

et al. 2020

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The synthesis of variously substituted indolo[2,3c]quinolin-6(7H)-ones was developed via Pd-catalyzed intramolecular C−H arylation. This method highlights a strategy for preparing indoloquinoline precursors bearing versatile functional groups and provides a new approach for the synthesis of antimalarial isoneocryptolepine analogues. The plausible ring closure mechanism was examined with quantum chemical calculations, where a trigonal bipyramidal concerted metalation− deprotonation transition state is presumable.

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Methods of synthesis of natural indoloquinolines isolated from Cryptolepis sanguinolenta

Cited by 19 publications

References 114 publications

Divergent Synthesis of Indolo[3,2- c]quinolines, Neocryptolepines and Related Tetracyclic Ring-Systems Containing Promising Biological Activities

Divergent Synthesis of Indolo[3,2- c]quinolines, Neocryptolepines and Related Tetracyclic Ring-Systems Containing Promising Biological Activities

Highly Antiproliferative Latonduine and Indolo[2,3-c]quinoline Derivatives: Complex Formation with Copper(II) Markedly Changes the Kinase Inhibitory Profile

Synthesis of Indolo[2,3-c]quinolin-6(7H)-ones and Antimalarial Isoneocryptolepine. Computational Study on the Pd-Catalyzed Intramolecular C–H Arylation

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