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

2019; Elsevier BV; Volume: 168; Linguagem: Inglês

10.1016/j.ejmech.2019.02.038

1768-3254

Ilhem Khelifi, Timothée Naret, Abdallah Hamzé, Jérôme Bignon, Hélène Levaïque, María Concepción García Alvarez, Joëlle Dubois, Olivier Provot, Mouâd Alami,

Cancer therapeutics and mechanisms

The synthesis and evaluation of a series of N,N-bis-heterocyclic-methylamines 1 as isoazaerianin analogues are described. It was demonstrated that the replacement of the 3,4,5-trimethoxyphenyl A-ring present in CA-4, isoCA-4 and 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 anti-cancer 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.