Design, Synthesis, and Biological Evaluation of 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3- d ]pyrimidines as Microtubule Targeting Agents.

A series of eleven 4-substituted 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3- d ]pyrimidines were designed and synthesized and their biological activities were evaluated. Synthesis involved the Gewald reaction to synthesize ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate ring, and S N Ar reactions. Compound 4 was 1.6- and ~7-fold more potent than the lead compound 1 in cell proliferation and microtubule depolymerization assays, respectively. Compounds 4 , 5 and 7 showed the most potent antiproliferative effects (IC 50 values < 40 nM), while compounds 6 , 8 , 10 , 12 and 13 had lower antiproliferative potencies (IC 50 values of 53-125 nM). Additionally, compounds 4 - 8 , 10 and 12 - 13 circumvented Pgp and β III-tubulin mediated drug resistance, mechanisms that diminish the clinical efficacy of paclitaxel (PTX). In the NCI-60 cell line panel, compound 4 exhibited an average GI 50 of ~10 nM in the 40 most sensitive cell lines. Compound 4 demonstrated statistically significant antitumor effects in a murine MDA-MB-435 xenograft model.