Microtubules (MTs), extensive polymers composed of αβ-tubulin heterodimers, are key components of the cellular cytoskeleton and have essential roles in cellular metabolism. Microtubule targeting agents (MTAs) are highly successful chemotherapeutic agents owing to their ability to target MT dynamics and interfere with critical cellular functions, including mitosis, cell migration and signaling, intracellular trafficking, and angiogenesis. However, the clinical utility of MTAs as cancer chemotherapeutics is often thwarted by dose limiting toxicities and the development of resistance. This necessitates the development of novel agents that have increased tumor selectivity and are insensitive to resistance mechanisms. MTAs that bind within the colchicine site circumvent P-glycoprotein (Pgp) efflux and βIII-tubulin mediated resistance. Previously, we have reported compounds 1 and 2 with a cyclopenta[d]pyrimidine and a thieno[2,3-d]pyrimidine scaffold, respectively, which bind to the colchicine site of tubulin and inhibit tubulin assembly. To further explore the structure-activity relationships of these compounds, we designed conformationally rigid analogs of the N4-aryl group in 1 and 2, respectively, while maintaining the parent thieno[2,3-d]pyrimidine scaffold. The designed analogs were synthesized, and biological evaluation showed that the compounds inhibit tubulin assembly and binding of colchicine to tubulin. The most potent compound had an IC50 in the nanomolar range against the MCF-7 breast cancer cell line. Thus, we have further identified bicyclic substituted thieno[2,3-d]pyrimidine as a structural scaffold for inhibition of tubulin assembly and colchicine binding, and compounds with this nucleus can have potent cytotoxic activity against the MCF-7 cell line. The design, molecular docking studies, synthesis, and biological activities of these analogs will be presented and discussed.

Design, synthesis and biological evaluation of substituted thieno[2,3-d]pyrimidines as microtubule targeting agents (MTAs)

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ACS Fall 2022

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