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

Eur J Med Chem 2019 Apr 16;168:176-188. Epub 2019 Feb 16.

BioCIS, Univ. Paris-Sud, CNRS, Université Paris-Saclay, 92290, Châtenay-Malabry, France. Electronic address:

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: IC = 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.

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http://dx.doi.org/10.1016/j.ejmech.2019.02.038DOI Listing
April 2019
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