Agents that interfere with microtubules, including the vinca alkaloids and the taxanes, are important antitumor agents. Despite the unprecedented success of these agents in cancer chemotherapy, multidrug resistance is a major limitation. We recently reported N-(4-methoxyphenyl)-N,5-dimethylfuro[2,3-d]pyrimidin-4-amine (1  ) as a potent antimitotic tubulin-binding agent. Compound 1  inhibited tubulin polymerization, the binding of [3H]colchicine to tubulin, and circumvented P-glycoprotein (Pgp) and �III-tubulin mediated resistance. Based on the anti-tubulin activity of 1  , we designed eight compounds with variations in the alkyl and aryl substituents at the N4-position. These analogs were synthesized by treating   the 4-amino analog with appropriate aryl iodides followed by N4-alkylation. The 4-amino analog was synthesized by treating 1-hydroxypropan-2-one with malononitrile followed by cyclization with formamidine hydrochloride. The synthesis and preliminary biological activity of these analogs will be presented.

Design, synthesis, and biological evaluation of substituted furo[2,3-<i>d</i>]pyrimidines as potent antimitotic agents that circumvent Pgp and <i>β</i>III-tubulin mediated resistance

244th National Meeting (2012)

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Design, synthesis, and biological evaluation of substituted furo[2,3-d]pyrimidines as potent antimitotic agents that circumvent Pgp and βIII-tubulin mediated resistance