N,N-bis-heteroaryl methylamines: Potent anti-mitotic and highly cytotoxic agents.
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.
['Khelifi|Ilhem|I|', 'Naret|Timothée|T|', 'Hamze|Abdallah|A|', 'Bignon|Jérome|J|', 'Levaique|Hélène|H|', 'Garcia Alvarez|Maria Concepcion|MC|', 'Dubois|Joëlle|J|', 'Provot|Olivier|O|', 'Alami|Mouad|M|']
D000970:Antineoplastic Agents D017209:Apoptosis D059447:Cell Cycle Checkpoints D049109:Cell Proliferation D003603:Cytotoxins D004305:Dose-Response Relationship, Drug D004354:Drug Screening Assays, Antitumor D045325:HCT116 Cells D006801:Humans D008744:Methylamines D008938:Mitosis D015394:Molecular Structure D013329:Structure-Activity Relationship D014407:Tumor Cells, Cultured
Cytotoxicity isoCA-4 Quinoline Quinazoline Carbazole Indole Cancer Tubulin