Microtubules are involved in a wide variety of cellular functions, including cellular transport, protein trafficking, and mitosis. Microtubule-targeting agents (MTAs) have gained significant interest as important targets for cancer therapy. Paclitaxel, podophyllotoxin, vinca alkaloids, and the epothilones are some examples of natural products which interfere with microtubule dynamics. Combretastatin A-4 phosphate (CA-4P, fosbretabulin) and A-1 diphosphate (CA-1P, OXi4503), 2-methoxyestradiol, and verubulin are a few of the colchicine site binding agents that have been evaluated in phase 1 and 2 clinical trials as anticancer agents alone and in combination with other drugs. Thus far, no colchicine site agent has been approved as an anticancer agent. Hence, this site provides new opportunities for drug discovery. The success of tubulin binding agents is limited by the emergence of multi-drug resistance mechanisms including the overexpression of P-glycoprotein and /or βIII- tubulin. We previously reported the design, synthesis, and antitumor activity of pyrrolo[3,2-d]pyrimidine (1), which inhibits tubulin assembly. Compound 1 also circumvented P- glycoprotein and βIII- tubulin mediated resistance. On the basis of the anti-tubulin activity of 1, we designed pyrazolo[4,3-d]pyrimidine analogs and their derivatives. Regioselectivity of pyrazolo compounds was determined by means of NOESY experiments, which showed a spatial closeness of the pyrazole hydrogen atom to the adjacent protons on appropriate substituents. The design, synthesis, structure-activity relationship, and biological evaluations of these agents will be presented and discussed.

Pyrazolo[4,3-d]pyrimidines: A novel scaffold for microtubule-targeting agents (MTAs)

256th National Meeting (2018)

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