Dynamic microtubules are involved in essential cellular processes, including mitosis, the trafficking of proteins, organelles, and RNA, cellular signaling and migration. Microtubule targeting agents (MTAs) disturb microtubule dynamics by altering αβ- tubulin heterodimer addition and loss from the microtubule, which disrupts microtubule-dependent cellular processes. The MTAs are divided into two classes: microtubule depolymerizing agents binding to either the vinca domain, the maytansine site or the colchicine site and microtubule polymerizing agents binding to the taxol site or the laulimalide/peloruside A site on the microtubule. The clinical efficacy of MTAs is limited by multidrug resistance due to expression of the P-glycoprotein drug efflux pump or increased expression of the βIII-isotype of tubulin. The development of MTAs that are effective against cell lines representative of these forms of drug resistance could have advantages in patients who fail to respond to current MTAs, such as paclitaxel. In general, MTAs that bind within the colchicine site circumvent Pgp and βIII-tubulin mediated resistance. However, no MTA that binds to this site is approved for the treatment of cancer. We have designed water soluble, colchicine site binding agents with different substitutions at the C2 and N4-positions of the pyrido[3,2-d]pyrimidine scaffold. The most potent compound inhibited tubulin assembly and had antiproliferative potency in the nanomolar range against the MDA-MD-435 melanoma cell lines. This compound retained efficacy in βIII-tubulin expressing HeLa cells (WTβIII), as well as Pgp-overexpressing SK-OV-3 MDR-1-M6/6 (M6/6) cells. The design, synthesis and biological activities of these analogs will be presented and discussed.

Design, synthesis, and structure-activity relationships of pyrido[3,2-d]pyrimidines as microtubule targeting agents that are effective against Pgp and βIII-tubulin overexpressing cancer cells

256th National Meeting (2018)

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