The synthesis and tubulin binding activity of thiophene-based analogues of combretastatin A-4.
A number of analogues of combretastatin A-4 (1), containing a thiophene ring interposed between the two phenyl groups, have been prepared. The synthesis of these compounds employed a combination of palladium-mediated coupling and iodocyclization techniques. The thiophene compounds 11, 14, 18, and 19 also represent non-benzofused analogues of some recently described tubulin binding benzo[b]thiophenes 3-5. The most active thiophene compounds identified in this study were 11, 14, and 18. Overall they are less active than 1 but exhibit comparable activity to the most active of the benzo[b]thiophenes 3-5. A structure-activity relationship of these compounds is considered.
Flynn
B L
BL
Department of Chemistry, The Faculties, Australian National University, Canberra, ACT 0200, Australia. flynn@rsc.anv.edu.au
Flynn
G P
GP
Hamel
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Jung
M K
MK
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy; D003078:Colchicine / Q000378:metabolism / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006139:Guaiacol / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D014404:Tubulin / Q000187:drug effects / Q000378:metabolism*; D014407:Tumor Cells, Cultured
C442387:2-(3-hydroxy-4-methoxyphenyl)-3-((3,4,5-trimethoxyphenyl)carbonyl)thiophene; C442386:2-(3-hydroxy-4-methoxyphenyl)-3-(3,4,5-trimethoxyphenyl)thiophene; D000970:Antineoplastic Agents; D013267:Stilbenes; D013876:Thiophenes; D014404:Tubulin; C051763:thiophene A; D006139:Guaiacol; C058728:fosbretabulin; D003078:Colchicine