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Synthesis and Structure–Activity Relationships of Constrained Heterocyclic Analogues of Combretastatin A4
Author(s) -
Arthuis Martin,
Pontikis Renée,
Chabot Guy G.,
Seguin Johanne,
Quentin Lionel,
Bourg Stéphane,
MorinAllory Luc,
Florent JeanClaude
Publication year - 2011
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201100154
Subject(s) - moiety , stereochemistry , chemistry , combretastatin , ring (chemistry) , lactone , oxindole , lactam , biological activity , heck reaction , structure–activity relationship , in vitro , tubulin , microtubule , biochemistry , organic chemistry , biology , catalysis , alkyl , aryl , microbiology and biotechnology
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.