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

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.

Cite this article as:

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