Abstract 2477: Design, synthesis and biological evaluation of substituted monocyclic pyrimidines as potent microtubule targeting antitumor agents that circumvent Pgp and βIII-tubulin-mediated resistance.

Abstract

Abstract Tubulin binding agents are the most effective drugs in p53 resistant cancer cell lines. Although microtubule disrupting agents like paclitaxel are highly successful, they have major limitations against multidrug resistance (MDR) tumors. Overexpression of P-glycoprotein (Pgp) and/or βIII-tubulin can severely limit their clinical utility as cancer chemotherapeutic agents. Antitubulin agents like paclitaxel and other taxoids also have poor water solubility, and this hampers their administration to patients since these compounds must be formulated with polyethoxylated castor oil. This medium can cause hypersensitivity reactions and requires prolonged administration times. Recently, we reported analogs with the pyrrolo[3,2-d]pyrimidine scaffold that circumvent these drawbacks. To explore the structure-activity relationships of these compounds, including simplification of the pyrrolo[3,2-d]pyrimidine scaffold, we designed conformationally flexible substituted monocyclic N-methyl-4-methoxyanilino pyrimidines 1-6 from the corresponding 4-chloro analogs by treatment with N-methyl-4-methoxyaniline followed by N6-alkylation for 2-6 . Compounds 1-6 inhibited tubulin assembly (4, IC50 = 1.5 ± 0.2 μM) and binding of colchicine to tubulin (4, 75% inhibition at 1 μM, 95% at 5 μM with 5 μM [3H]colchicine). Four of these compounds inhibited the growth of human cancer cells in culture with nanomolar IC50’s from 15 to 62 nM. These compounds are also active in paclitaxel resistant tumor cells overexpressing either βIII-tubulin or Pgp, thus apparently overcoming two important mechanisms associated with clinical resistance to paclitaxel. Thus, we have identified simplified substituted monocyclic pyrimidines containing a novel structural scaffold for inhibition of tubulin assembly and colchicine binding and which have potent cytotoxic activity against human cancer cells in culture. Citation Format: Aleem Gangjee, Rishabh Mohan, Ernest Hamel, Ruoli Bai. Design, synthesis and biological evaluation of substituted monocyclic pyrimidines as potent microtubule targeting antitumor agents that circumvent Pgp and βIII-tubulin-mediated resistance. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2477. doi:10.1158/1538-7445.AM2013-2477