title: Design and synthesis of silicon-containing tubulin polymerization inhibitors: replacement of the ethylene moiety of combretastatin A-4 with a silicon linker.
abstract: Silicon-containing combretastatin analogs were designed, synthesized and evaluated for stability and biological activities. Among them, compound 31 exhibited strong tubulin polymerization-inhibitory activity and very potent tumor cell growth-inhibitory activity (IC50=0.007 μM) in MCF-7 cell proliferation assay. This compound also potently inhibited [(3)H]colchicine binding (90.7% inhibition at 3 μM). These activities were comparable to those of combretastatin A-4 (CA-4) (1). In addition, compound 31 was physico-chemically more stable than 1. These results suggest that a silicon linker can act as a bioisoster of a cis carbon-carbon double bond.
authors.affiliation: Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan. Electronic address: nakamura-nk@iam.u-tokyo.ac.jp.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Nakamura
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kajita
authors.forename: Yotaro
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hashimoto
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D045744:Cell Line, Tumor; D003078:Colchicine / Q000378:metabolism; D015195:Drug Design; D005260:Female; D006801:Humans; D012825:Silicon / Q000737:chemistry / Q000494:pharmacology; D013267:Stilbenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism*; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D013267:Stilbenes; D014404:Tubulin; D050257:Tubulin Modulators; C058728:fosbretabulin; D003078:Colchicine; D012825:Silicon
keywords: Antitumor agent; Colchicine; Combretastatin; Silicon; Tubulin