In the arsenal of anticancer therapies, microtubule targeting agents (MTAs) embody some of the most successful first-line treatments used. MTAs function by disrupting microtubule dynamics that a cancer cell depends on for varied cellular processes: intracellular trafficking of proteins, organelles, and RNA, mitosis, maintenance of cell morphology, cellular signaling and migration. The interference with microtubule dynamics is caused by either stabilizing or destabilizing microtubules, defining the two classes of MTAs. Microtubule stabilizing taxanes and microtubule destabilizing vinca alkaloids are the most important MTAs used in cancer treatment. However, they are limited in efficacy by their poor water solubility and occurrence of resistance due to overexpression of the drug efflux pump (P-glycoprotein) or increased expression of the βIII-isotype of tubulin. Colchicine site binding agents like combretastatin A-4 (CA-4) circumvent these resistance mechanisms. However, there are no FDA approved inhibitors targeting the colchicine site, underscoring the need for novel colchicine site binding MTAs. Recently, we reported the design and synthesis of a novel series of MTAs: pyrazolo[4,3-d]pyrimidines, using a scaffold-hopping approach. Based on the success of this scaffold both in vitro and in vivo, we have designed analogs to study the structure-activity relationship of this chemotype. Modifications in the N4-aniline moiety and in the substituents on the scaffold have been explored. The design, synthesis and biological activities of these analogs will be presented and discussed.

Design, synthesis, structure-activity relationship and evaluation of pyrazolo[4,3-d]pyrimidines as colchicine-site binding microtubule targeting agents (MTAs) that mitigate multidrug resistance in cancer

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ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.