Synthesis and structure-activity relationships of constrained heterocyclic analogues of combretastatin A4.

Abstract : A series of combretastatin A4 (CA4) analogues with a lactam or lactone ring fused to the trimethoxyphenyl or the B-phenyl moiety were synthesized in an efficient and stereoselective manner by using a domino Heck-Suzuki-Miyaura coupling reaction. The vascular-disrupting potential of these conformationally restricted CA4 analogues was assessed by various in vitro assays: inhibition of tubulin polymerization, modification of endothelial cell morphology, and disruption of endothelial cell cords. Compounds were also evaluated for their growth inhibitory effects against murine and human tumor cells. B-ring-constrained derivatives that contain an oxindole ring (in contrast to compounds with a benzofuranone ring) as well as analogues bearing a six-membered lactone core fused to the trimethoxyphenyl ring are endowed with significant biological activity. The most potent compound of this series (oxindole 9 b) is of particular interest, as it combines chemical stability and a biological activity profile characteristic of a vascular-disrupting agent.
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Submitted on : Tuesday, July 24, 2012 - 4:47:27 PM
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Martin Arthuis, Renée Pontikis, Guy G Chabot, Johanne Seguin, Lionel Quentin, et al.. Synthesis and structure-activity relationships of constrained heterocyclic analogues of combretastatin A4.. ChemMedChem, Wiley-VCH Verlag, 2011, 6 (9), pp.1693-705. ⟨10.1002/cmdc.201100154⟩. ⟨hal-00720508⟩

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