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Anti-Cancer Agents in Medicinal Chemistry


ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Discovery and Hit to Lead Optimization of Novel Combretastatin A-4 Analogues: Dependence of C-Linker Length and Hybridization

Author(s): Olivier Provot, Abdallah Hamze, Jean-François Peyrat, Jean-Daniel Brion and Mouad Alami

Volume 13 , Issue 10 , 2013

Page: [1614 - 1635] Pages: 22

DOI: 10.2174/187152061310131206162302

Price: $65


We have synthesized a large variety of CA-4 analogues having a non-isomerizable C-linker between the A- and B-aromatic rings. Most of them displayed a nanomolar level of cytotoxicity against a panel of human cancer cell lines and inhibited tubulin polymerization at a micromolar level. Among all these compounds, the most interesting compounds were undoubtedly isoCA-4 and structural analogues 18-20 as well as benzil derivatives 11 which displayed a comparable level of activity than that of CA-4. Moreover, it has been demonstrated that these drugs arrested cancer cells in the G2/M phase of cellular cycle and induced apoptosis at very low concentrations. In vitro antivascular effects and the binding mode of the most active compounds was also investigated.

Keywords: Apoptosis, binding, combretastatin A-4, isoCA-4, cytotoxicity, linker, tubulin.

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