Role of basic aminoalkyl chains in the lead optimization of Indoloquinoline alkaloids

Nuthakki, Vijay K.; Mudududdla, Ramesh; Bharate, Sandip B.

doi:10.1016/j.ejmech.2021.113938

Cited by 11 publications

(6 citation statements)

References 83 publications

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“…Although intense efforts have been put towards unraveling the antiproliferative potential of indoloquinoline alkaloids, they have thus far not made it to human clinical trials. [35] Regardless, several promising antiproliferative results have been reported in the literature. Similarly, to the antiplasmodial activities discussed previously, the inclusion of a basic alkylamino chain onto the indoloqunoline scaffold has also shown promise for antiproliferation, with observed IC 50 values similar to those for doxorubicin (MV4-11: IC 50 = 0.0060 μM; A549: IC 50 = 0.33 μM; HCT116: IC 50 = 0.39 μM).…”

Section: Anticancer Activity Of Indoloquinolines In the Literaturementioning

confidence: 99%

Regiodivergent Synthesis and Biological Activities of Indoloquinoline Based Compounds

Håheim,

Sydnes

2024

The Chemical Record

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Cryptolepine, neocryptolepine, and isocryptolepine have remained popular synthetic targets ever since their isolation from the aqueous extracts of the West African climbing shrub Cryptolepis sanguinolenta. These natural alkaloids were found to contain significant antimalarial, antiproliferative and antimicrobial activities, making them ideal starting points for the development of novel drug candidates. As natural product synthesis is often plagued with step‐heavy procedures and poor atom economy, the discovery of synthetic protocols addressing these concerns are sorely needed. In our laboratories, we have devoted our efforts into the development of regiodivergent synthesis whereby two of the indoloquinoline natural products, namely neocryptolepine and 11H‐indolo[3,2‐c]quinolines, could be assembled in only a few steps from a common and readily available starting material. Our synthetic endeavors to meet these goals include a cascade palladium‐catalyzed Suzuki‐Miyuara cross‐coupling and intramolecular C−N bond formation and a photochemical nitrene insertion strategy. Furthermore, our methods also allowed for the construction of several diversely functionalized natural product derivatives which were subjected to biological evaluations.

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Section: Anticancer Activity Of Indoloquinolines In the Literaturementioning

confidence: 99%

Regiodivergent Synthesis and Biological Activities of Indoloquinoline Based Compounds

Håheim,

Sydnes

2024

The Chemical Record

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“…Further research showed 5 exhibited cytotoxcity and anti-plasmodial activity. Thus, as a promising natural product, literature about 5 and its derivatives is emerging (Lavrado et al, 2010;Wang et al, 2019;Nuthakki et al, 2022).…”

Section: Natural Occurring α-Carbolinesmentioning

confidence: 99%

Comprehensive review of α-carboline alkaloids: Natural products, updated synthesis, and biological activities

Yang

et al. 2022

Front. Chem.

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α-carboline (9H-pyrido[2,3-b]indole), contains a pyridine ring fused with an indole backbone, is a promising scaffold for medicinal chemistry. In recent decades, accumulating evidence shows that α-carboline natural products and their derivatives possess diverse bioactivities. However, hitherto, there is no comprehensive review to systematically summarize this important class of alkaloids. In this perspective, this paper represents the first review to provide a comprehensive description of α-carbolines including natural products, updated literature of synthesis, and their diverse biological activities. Their biological activities including antitumor, anti-microbial, anti-Alzheimer’s disease, anti-atherosclerosis, and antioxidant activities were hilighted. And the targets and the main structure activity relationships (SARs) will be presented. Finally, challenges and future directions of this class of compounds will be discussed. This review will be helpful in understanding and encouraging further exploration for this group of alkaloids.

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“…Although enormous efforts have been put into investigating the potential antiproliferative properties of the indoloquinoline alkaloids, they have never made it to human clinical trials, thus further endeavours are required to unlock their full therapeutic potential. [88] Table 1.1: Antiproliferative activities of indoloquinolines 24A, 24B and 38A against normal mice cell fibroblasts BALB/3T3 and against cancer cell lines MV4-11, A549 and HCT116.…”

Section: Cancermentioning

confidence: 99%

“…Further, the complexes containing such nitrogen-donor ligands have found applications as catalysts for cyclopropanations, allylic substitutions, various C-C and C-N cross-coupling reactions, addition reactions, among others. [155] Figure 3.1: Nitrogen-donor chelating ligands 2,2'-bipyridine (86), 2,2'-biquinoline (87) and 1,10-phenanthroline (88). [155,159] With this in mind, it was envisaged that the prepared biquinoline L1 could be reacted with a transition metal salt, ML 2 , to give rise to both bidentate and tridentate complexes (Scheme 25).…”

Section: Design Of Biquinoline Ligands For Catalysismentioning

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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Role of basic aminoalkyl chains in the lead optimization of Indoloquinoline alkaloids

Cited by 11 publications

References 83 publications

Regiodivergent Synthesis and Biological Activities of Indoloquinoline Based Compounds

Regiodivergent Synthesis and Biological Activities of Indoloquinoline Based Compounds

Comprehensive review of α-carboline alkaloids: Natural products, updated synthesis, and biological activities

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

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