title: Synthesis and evaluation of stilbene and dihydrostilbene derivatives as potential anticancer agents that inhibit tubulin polymerization.
abstract: An array of cis-, trans-, and dihydrostilbenes and some N-arylbenzylamines were synthesized and evaluated for their cytotoxicity in the five cancer cell cultures A-549 lung carcinoma, MCF-7 breast carcinoma, HT-29 colon adenocarcinoma, SKMEL-5 melanoma, and MLM melanoma. Several cis-stilbenes, structurally similar to combretastatins, were highly cytotoxic in all five cell lines and these were also found to be active as inhibitors of tubulin polymerization. The most active compounds also inhibited the binding of colchicine to tubulin. The most potent of the new compounds, both as a tubulin polymerization inhibitor and as a cytotoxic agent, was (Z)-1-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)ethene (5a). This substance was almost as potent as combretastatin A-4 (1a), the most active of the combretastatins, as a tubulin polymerization inhibitor. Compound 5a was found to be approximately 140 times more cytotoxic against HT-29 colon adenocarcinoma cells and about 10 times more cytotoxic against MCF-7 breast carcinoma cells than combretastatin A-4. However, 5a was found to be about 20 times less cytotoxic against A-549 lung carcinoma cells, 30 times less cytotoxic against SKMEL-5 melanoma cells, and 7 times less cytotoxic against MLM melanoma cells than combretastatin A-4. The relative potencies 5a greater than 8a greater than 6a for the cis, dihydro, and trans compounds, respectively, as inhibitors of tubulin polymerization are in agreement with the relative potencies previously observed for combretastatin A-4 (1a), dihydrocombretastatin A-4 (1c), and trans-combretastatin A-4 (1b). The relative potencies 5a greater than 8a greater than 6a were also reflected in the results of the cytotoxicity assays. Structure-activity relationships of this group of compounds are also discussed.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, Purdue University, West Lafayette, Indiana 47907.
authors.forename: M
authors.initials: M
authors.lastname: Cushman
authors.forename: D
authors.initials: D
authors.lastname: Nagarathnam
authors.forename: D
authors.initials: D
authors.lastname: Gopal
authors.forename: A K
authors.initials: AK
authors.lastname: Chakraborti
authors.forename: C M
authors.initials: CM
authors.lastname: Lin
authors.forename: E
authors.initials: E
authors.lastname: Hamel
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy; D055598:Chemical Phenomena; D002621:Chemistry; D003078:Colchicine / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D008545:Melanoma / Q000188:drug therapy; D015394:Molecular Structure; D011108:Polymers / Q000378:metabolism; D013267:Stilbenes / Q000138:chemical synthesis* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D011108:Polymers; D013267:Stilbenes; D014404:Tubulin; D050257:Tubulin Modulators; C070486:1-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)ethene; C058728:fosbretabulin; D003078:Colchicine