Abstract
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.
Anti-Cancer Agents in Medicinal Chemistry
Title:Discovery and Hit to Lead Optimization of Novel Combretastatin A-4 Analogues: Dependence of C-Linker Length and Hybridization
Volume: 13 Issue: 10
Author(s): Olivier Provot, Abdallah Hamze, Jean-François Peyrat, Jean-Daniel Brion and Mouad Alami
Affiliation:
Keywords: Apoptosis, binding, combretastatin A-4, isoCA-4, cytotoxicity, linker, tubulin.
Abstract: 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.
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Provot Olivier, Hamze Abdallah, Peyrat Jean-François, Brion Jean-Daniel and Alami Mouad, Discovery and Hit to Lead Optimization of Novel Combretastatin A-4 Analogues: Dependence of C-Linker Length and Hybridization, Anti-Cancer Agents in Medicinal Chemistry 2013; 13 (10) . https://dx.doi.org/10.2174/187152061310131206162302
DOI https://dx.doi.org/10.2174/187152061310131206162302 |
Print ISSN 1871-5206 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5992 |
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