Tubulin inhibitors. Synthesis and biological activity of HTI-286 analogs with B-segment heterosubstituents |
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Authors: | Niu Chuan Smith Daniel Zask Arie Loganzo Frank Discafani Carolyn Beyer Carl Greenberger Lee Ayral-Kaloustian Semiramis |
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Institution: | Chemical and Screening Sciences, Discovery Medicinal Chemistry, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, USA. niuc@wyeth.com |
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Abstract: | Modifications of the B-segment of HTI-286 (2) produced a class of analogs incorporating heteroatom-substituents. The structure-activity relationship was studied. Analogs bearing methylsulfide and fluoride groups exhibited potency comparable to that of the parent compound HTI-286 and to paclitaxel in cytotoxicity assays against KB-3-1 cell lines. These analogs were more potent than paclitaxel against P-glycoprotein expressing KB-8-5 and KB-V1 cell lines. Several analogs showed strong inhibition of tubulin polymerization. |
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