Microtubules play a major role in mitosis, and this makes microtubule disrupting agents like paclitaxel highly active cancer chemotherapeutic agents. Resistance due to overexpression of Pgp and/or �-III-tubulin severely limits the clinical utility of these drugs as anticancer agents. The combination of cytotoxic antitubulin activity with cytostatic antiangiogenic activity might provide agents with chemotherapeutic potential which in turn could circumvent or delay tumor cell resistance. Such dual acting agents also need not be highly potent so as to circumvent serious toxicity issues compared with potent cytotoxic agents. We reported analogs with the pyrrolo[3,2-d]pyrimidine scaffold with such dual activities. To simplify this scaffold, conformationally flexible substituted monocyclic N-methyl-4-methoxyanilino pyrimidines were designed with tubulin inhibition (cytotoxic) as well as VEGFR-2 kinase inhibition (antiangiogenic) in single molecules. The design, synthesis and structure activity relationship of these agents will be presented.

Design, synthesis, and biological evaluation of substituted monocyclic pyrimidines with dual antiangiogenic and cytotoxic antitubulin activities as antitumor agents

246th National Meeting (2013)

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