Abstract 4553: Substituted monocyclic pyrimidines as potent tubulin inhibitors that circumvent P-glycoprotein mediated resistance

Abstract

Abstract Tubulin is involved in several critical cellular functions, including cell division, cell motility and development and maintenance of cell shape. Although microtubule disrupting agents like paclitaxel are highly successful chemotherapeutic agents, these compounds are easily recognized by P-glycoprotein (Pgp) and are pumped out of cancer cells, resulting in resistance to the agent. Thus, these compounds have major limitations against multidrug resistant tumors. Recently, we reported simple, monocyclic pyrimidines with the N-methyl-4′-methoxyaniline moiety at the 4-position. These compounds circumvent some of the important limitations of paclitaxel while preserving its antimitotic activity. To further evaluate the SAR at the 4-position of the pyrimidine scaffold, a series of compounds were designed and synthesized that involved replacing the chloro moiety of the 5-amino-4,6-dichloro-2-methylpyrimidine with various anilines. The replacement of the N-methyl-4′-methoxyaniline moiety of the lead molecule with a conformationally restricted 6′-methoxy-tetrahydroquinoline moiety resulted in potent tubulin assembly inhibition (IC50 = 3.0 ± 0.03 μM) comparable to that observed with combretastatin A-4 (CSA4, IC50 = 1.1 ± 0.1 μM), of which the phosphorylated derivative is currently in clinical trials. It is a potent inhibitor of [3H]colchicine binding (65% at 5 μM concentration) indicating that it binds at the colchicine binding site on tubulin similar to CSA4. Similarly, the monocyclic pyrimidine with a conformationally restricted 4-N-methyl 2′,3′-dihydrobenzofuran moiety was also a potent inhibitor of bovine tubulin assembly. Replacement of the 4′-methoxy of the lead with a 4′-thiomethyl retained potency against tubulin assembly (IC50 = 2.6 ± 0.1 μM). In Pgp overexpressing NCI/ADR-RES cell line, three of the newly synthesized compounds were found to be 1.5-5-fold more potent (IC50 = 170-630 nM) than in the wild type OVCAR-8 cell line, thus, overcoming an important mechanism associated with clinical resistance to paclitaxel. These attributes of the 4-N-substituted monocyclic pyrimidines provide the impetus for further preclinical development of these compounds. Citation Format: Rishabh Mohan, Aleem Gangjee, Ruoli Bai, Ernest Hamel. Substituted monocyclic pyrimidines as potent tubulin inhibitors that circumvent P-glycoprotein mediated resistance. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4553. doi:10.1158/1538-7445.AM2015-4553