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

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


Volume 16, 12 Issues, 2016


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Anti-Cancer Agents in Medicinal Chemistry

Formerly: Current Medicinal Chemistry - Anti-Cancer Agents

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  • 27th of 59 in Chemistry, Medicinal

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Editor-in-Chief:
Michelle Prudhomme
Universite Blaise Pascal - C.N.R.S
Aubiere Cedex
France


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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, 13(10): 1614-1635.

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

Affiliation: Univ. Paris-Sud 11, CNRS, BioCIS-UMR 8076, LabEx LERMIT, Laboratoire de Chimie Thérapeutique, Faculté de Pharmacie, 5 rue J.-B. Clément, Châtenay-Malabry, F-92296, France.

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.



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Article Details

Volume: 13
Issue Number: 10
First Page: 1614
Last Page: 1635
Page Count: 22
DOI: 10.2174/187152061310131206162302
Price: $58
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