Despite the unprecedented success of microtubule disrupting agents in cancerchemotherapy, multidrug resistance (MDR) is a major limitation of cancerchemotherapy, and MDR tumors are usually resistant to tubulin-binding drugs. Ourefforts in the design of multiple RTK-inhibitors to elucidate the plausible binding modes of our compounds led to the discovery of highly potent antimitotic antitumor agents that bind to the colchicine-binding site of tubulin and also overcome clinically relevant mechanisms of drug resistance: P-glycoprotein and �III-Tubulin mediated resistance. Conformationally restricted pyrrolo[3,2-d]pyrimidine analogs of the leadcompounds were designed and synthesized. These compounds inhibited microtubulepolymerization and had GI50's which were two-digit nanomolar against tumor cells in the NCI 60 human tumor cell line anticancer drug screen. The design, synthesis and biological activities of these analogs will be presented.

Design,
synthesis and biological evaluation of novel, conformationally restricted, water soluble, substituted pyrrolo[3,2-<i>d</i>]pyrimidines as antitubulin antitumor agents

242nd National Meeting (2011)

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Design, synthesis and biological evaluation of novel, conformationally restricted, water soluble, substituted pyrrolo[3,2-d]pyrimidines as antitubulin antitumor agents