N,N-bis-heteroaryl methylamines: Potent anti-mitotic and highly cytotoxic agents

Abstract

O.P.) and/or mouad.alami@u-psud.fr (M.A.) ‡ These authors contributed equally Abstract The synthesis and evaluation of a series of N,N-bis-heterocyclic-methylamines 1 as isoazaerianin analogues are descriebed. It was demonstrated that the replacement of the 3,4,5-trimethoxyphenyl A-ring present in CA-4, isoCA-4and isoazaerianin by a quinoline or a quinazoline ring is possible and often beneficiary for a high level of cytotoxicity.We have also showed that a carbazole or an indole nucleus are very effective as B-rings in this series, leading to anticancer drugs 1 having a sub-nanomolar level of cytotoxicity (1a: IC50 = 70 pM against HCT116 cells). 1a also display a high level of cytotoxicity against four other human cancer cells and inhibited tubulin assembly at a micromolar level.Moreover, at a concentration of 5 nM, 1a arrested the cellular cycle in G2/M phase of the cellular cycle and induced apoptosis of HCT116 cells. It was also showed that after few hours 1a at a concentration of 10 nM totally disrupted endothelial network formation on Matrigel.

Target-based anticancer indole derivatives and insight into structure‒activity relationship: A mechanistic review update (2018–2021)

“…Also, QnisoCz 18 was 67 times more cytotoxic than CA-4 against lung adenocarcinoma epithelial cells (A549). A similar replacement as in compound 18 was also achieved with a N (Me) linker in compound 19 59 . In order to continue studying SARs in the isoCA-4 series, and inspired by the promising results obtained with quinolines and quinazolines, the current study was undertaken to investigate the effect of novel bridge structure variations on the antiproliferative activities of the resulting CA-4 analogues.…”

Cyclic bridged analogs of isoCA-4: Design, synthesis and biological evaluation

“…A similar replacement as in compound 11 was also achieved with a N(Me) linker in compound 12. [28] In the continuation of our work in the study of SARs of isoCA-4 series and encouraged by the exciting results obtained with quinolines and quinazolines, we undertake the current study to investigate the effect of novel variation of bridge structure on the antiproliferative activities of the resulting CA-4 analogs. Precisely, we have designed, synthesized, and evaluated a series of novel cyclic bridged analogs (CBAs) of CA-4 having a phenyl or a pyridine linker (Fig.…”

Anticancer properties of indole derivatives as IsoCombretastatin A-4 analogues

“…Structure-activity relationships (SARs) also revealed that various non-isomerizable linkers of small size are welcome [13] of which the N-Methyl group predominated (e.g., azaFisoerianin 4). [27] Finally, it was demonstrated that the classical 3,4,5-trimethoxyphenyl (TMP) A-ring of CA-4 and isoCA-4 could be advantageously replaced by heterocycles as quinazolines [28] or quinolines [29] to promote highly cytotoxic analogues 6 [30] and 7 [31] having in structures a carbazole nucleus as B-ring. Herein, we were interested in synthesizing and evaluating the cytotoxicity of target molecules of type pyrido [1,2-a]indoles 11 [32] depicted in Scheme 1, which could be seen as analogues of carbazole compounds 5-7 [33,34] by connecting the nitrogen atom N1 to the carbon atom C2 in the carbazole system.…”