Synthesis and Evaluation of the Tetracyclic Ring-System of Isocryptolepine and Regioisomers for Antimalarial, Antiproliferative and Antimicrobial Activities

Håheim, Katja S.; Lindbäck, Emil; Tan, Kah Ni; Albrigtsen, Marte; Helgeland, Ida T. Urdal; Lauga, Clémence; Matringe, Théodora; Kennedy, Emily K.; Andersen, Jeanette Hammer; Avery, Vicky M.; Sydnes, Magne O.

doi:10.3390/molecules26113268

Cited by 9 publications

(32 citation statements)

References 81 publications

(149 reference statements)

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“…Conditions: PdCl 2 (dppf) (20 mol%), IMes (5 mol%), H 2 O 2 (35 wt%, 29 mol%), AcOH, MW sealed tube, 118 °C; n. f. = not formed. [132,149]…”

Section: Mw-assisted Intramolecular Cyclizations To Give Tetracyclesmentioning

confidence: 99%

“…Subjecting the newly formed aryl azide to thermolysis in boiling 1,2-dichlorobenzene, surprisingly resulted in formation of novel pyridocarbazole 61 and only trace amounts of pyridophenanthridine 54. [149] Scheme 17: Synthesis of the missing pyridocarbazole 61 using a azidation-nitrene-insertion approach. [149] The successful fomation of pyridocarbazole 61 could be determined by carefully elucidating all the signals of its NMR spectra.…”

Section: Divergent Synthesis Of Pyridophenanthridines 54 and Pyridoca...mentioning

confidence: 99%

“…[149] Scheme 17: Synthesis of the missing pyridocarbazole 61 using a azidation-nitrene-insertion approach. [149] The successful fomation of pyridocarbazole 61 could be determined by carefully elucidating all the signals of its NMR spectra. Characteristically, the proton at 8.84 ppm (J = 4.1 Hz, 1.4 Hz), appearing as a doublet of doublets is easily placed as H-3 based on its proximity to a heteroatom, as evident by its coupling constants (Figure 2.5).…”

Section: Divergent Synthesis Of Pyridophenanthridines 54 and Pyridoca...mentioning

confidence: 99%

“…Scheme 18: Synthesis of indoloquinolines 38 and 26 via installation of an azido moiety followed by thermal decomposition. [149] Having discovered conditions which allowed for the formation of pyridocarbazole 61 from biaryl 72, it was now possible to assemble both this scaffold along with pyridophenanthridine 54 from one common intermediate by using two different sets of reaction conditions, Path A and Path B, respecitvely (Scheme 19). Reaction procedures which can grant access to two compounds of interest from a common starting material or intermediate are highly sought after in synthetic chemistry, as they allow for more efficient access to desirable targets in an atom economic fashion.…”

Section: Divergent Synthesis Of Pyridophenanthridines 54 and Pyridoca...mentioning

confidence: 99%

“…[152] Scheme 19: Divergent synthesis of pyridophenanthridine 54 and pyridocarbazole 61 from common intermediate 72I. [149] Wanting to also prepare some functionalized derivatives of novel pyridocarbazole 61, a fluoro-substituted phenyl boronic acid pinacol ester was prepared using a standard Masuda borylation approach (Scheme 20). The obtained boronate was then treated with 5-bromoquinoline (67d) using our Suzuki-Miyaura cross-coupling protocol, furnishing biaryl 72b in excellent yield.…”

Section: Divergent Synthesis Of Pyridophenanthridines 54 and Pyridoca...mentioning

confidence: 99%

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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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“…Conditions: PdCl 2 (dppf) (20 mol%), IMes (5 mol%), H 2 O 2 (35 wt%, 29 mol%), AcOH, MW sealed tube, 118 °C; n. f. = not formed. [132,149]…”

Section: Mw-assisted Intramolecular Cyclizations To Give Tetracyclesmentioning

confidence: 99%

Section: Divergent Synthesis Of Pyridophenanthridines 54 and Pyridoca...mentioning

confidence: 99%

Section: Divergent Synthesis Of Pyridophenanthridines 54 and Pyridoca...mentioning

confidence: 99%

Section: Divergent Synthesis Of Pyridophenanthridines 54 and Pyridoca...mentioning

confidence: 99%

Section: Divergent Synthesis Of Pyridophenanthridines 54 and Pyridoca...mentioning

confidence: 99%

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

Håheim¹

2022

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DABCO‐Promoted Selective Photochemical C−N Coupling: Access to Unsymmetrical Azahelicenes

Balakhonov,

Mekeda,

Shirinian

2023

Adv Synth Catal

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A multifaceted study on the effect of various factors on the efficiency of photocyclization of naphthofuran O‐acyl oximes was performed. It showed that without any additives or in the presence of electron acceptors, the reaction occurs by a radical pathway and with low chemoselectivity, while DABCO promotes intramolecular cyclization to give naphthofuroquinolines (NFQs) in 34‐87% yields. The iminyl radical formed under UV irradiation in the presence of DABCO due to single electron transfer (SET) and N–O bond cleavage undergoes selective intramolecular homolytic aromatic substitution (HAS) with formation of a new C–N bond. This route to quinoline‐annulated scaffolds is based on the use of DABCO both as an electron transfer agent and a proton acceptor.

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Regiodivergent Synthesis of 11H‐Indolo[3,2‐c]quinolines and Neocryptolepine from a Common Starting Material

2023

Self Cite

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A large number of diversely functionalized analogs of the bioactive natural products neocryptolepine and isocryptolepine have been prepared from a series of 3-bromoquinoline derivatives. The neocryptolepines were obtained by a Pd 0catalyzed CÀ C bond coupling followed by CÀ N bond formation in yields up to 80 %, whereas the indoloquinolines were prepared by a Suzuki-Miyaura cross-coupling followed by azidation-photochemical cyclization in yields ranging from traces to 95 % yield.

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Synthesis and Evaluation of the Tetracyclic Ring-System of Isocryptolepine and Regioisomers for Antimalarial, Antiproliferative and Antimicrobial Activities

Cited by 9 publications

References 81 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

DABCO‐Promoted Selective Photochemical C−N Coupling: Access to Unsymmetrical Azahelicenes

Regiodivergent Synthesis of 11H‐Indolo[3,2‐c]quinolines and Neocryptolepine from a Common Starting Material

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