title: 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.
authors: Institut Curie, Centre de Recherche, 26 Rue d'Ulm, Paris 75248 Cedex 05, France.
authors: Martin
authors: M
authors: Arthuis
authors: Renée
authors: R
authors: Pontikis
authors: Guy G
authors: GG
authors: Chabot
authors: Johanne
authors: J
authors: Seguin
authors: Lionel
authors: L
authors: Quentin
authors: Stéphane
authors: S
authors: Bourg
authors: Luc
authors: L
authors: Morin-Allory
authors: Jean-Claude
authors: JC
authors: Florent
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002384:Catalysis; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D010165:Palladium / Q000737:chemistry; D013267:Stilbenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D006571:Heterocyclic Compounds; D013267:Stilbenes; D014404:Tubulin; D010165:Palladium; C058728:fosbretabulin