Agents that interfere with microtubule functions are important antitumor agents. Antiangiogenic agents target tumor angiogenic mechanisms that are vital for tumor growth and metastasis. Antiangiogenic agents are usually not tumoricidal but are mainly cytostatic. Combination chemotherapy with antiangiogenic and cytotoxic agents have shown significant promise and several studies with such combinations are in progress in the clinic. Single agents with both antiangiogenic activities as well as cytotoxicity would afford single agents that would circumvent pharmacokinetic problems of multiple agents, would avoid drug-drug interactions, could be used at lower doses to alleviate toxicity, could be devoid of overlapping toxicities, and could delay or prevent tumor cell resistance. We have designed, synthesized and evaluated novel pyrrolo[3,2-d]pyrimidines that inhibit both vascular endothelial growth factor receptor-2 (VEGFR-2) for antiangiogenic effects and tubulin for cytotoxic effects in single agents. These agents afford combination chemotherapeutic potential in single agents.  We have identified a compound with potent anticancer activity in aggressive basal like breast cancer (BLBC) and triple negative breast cancer (TNBC) lines. It also showed sensitivity in taxol resistant cells indicating that they are unlikely to be Pgp or MRP substrates [unlike taxol] and possesses relative selectivity of kill on tumor versus normal cell types. It reduces tumor size in vivo and vascularity in two flank xenograft models in mice and rats, superior to docetaxel and sunitinib, without overt toxicity to the animals. The design, synthesis and biological activities of these analogs will be presented.

Design, synthesis, and preclinical evaluation of 7-benzyl -N-substituted phenyl-5H-pyrrolo[3,2-d]pyrimidin-4-amines as single agents with antitubulin and antiangiogenic activity as antitumor agents

244th National Meeting (2012)

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