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

European Journal of Medicinal Chemistry
Ilhem KhelifiMouad Alami

Abstract

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.

References

Jan 1, 1990·Cancer Chemotherapy and Pharmacology·A T McGown, B W Fox
Mar 1, 1973·Proceedings of the National Academy of Sciences of the United States of America·M L ShelanskiC R Cantor
Jan 5, 1999·Bioorganic & Medicinal Chemistry Letters·K OhsumiT Tsuji
Sep 20, 2001·Proceedings of the National Academy of Sciences of the United States of America·R B LichtnerU Klar
Apr 4, 2003·Analytical Biochemistry·Donna M BarronSusan Bane
Jun 17, 2003·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Gordon J S RustinPatricia M Price
Dec 4, 2003·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·James P StevensonPeter J O'Dwyer
May 26, 2006·Journal of Medicinal Chemistry·Gian Cesare TronArmando A Genazzani
Sep 25, 2007·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Silvio AprileGiorgio Grosa
May 15, 2008·Bioorganic & Medicinal Chemistry Letters·Céline MoussetMouâd Alami
Mar 2, 2011·ChemMedChem·Samir MessaoudiMouad Alami
Jan 29, 2013·European Journal of Medicinal Chemistry·Evelia RasolofonjatovoMouad Alami
Apr 1, 2014·European Journal of Medicinal Chemistry·Mohamed Ali SoussiMouad Alami
Jun 16, 2015·ChemMedChem·Mohamed Ali SoussiMouad Alami
Feb 9, 2017·European Journal of Medicinal Chemistry·Ilhem KhelifiMouad Alami

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Citations

Oct 11, 2020·European Journal of Medicinal Chemistry·Shannon PecnardAbdallah Hamze
Dec 18, 2020·European Journal of Medicinal Chemistry·Raquel ÁlvarezRafael Peláez
Feb 24, 2021·Bioorganic Chemistry·Pratibha Yadav, Kamal Shah
Jun 26, 2021·European Journal of Medicinal Chemistry·Shannon PecnardOlivier Provot
Feb 18, 2020·European Journal of Medicinal Chemistry·Abdallah HamzeOlivier Provot

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