Abstract 3244: Design, synthesis and biological evaluation of substituted furo[2,3-d]pyrimidines as potent microtubule targeting antitumor agents that circumvent Pgp and βIII-tubulin mediated resistance

Abstract

Abstract Despite the unprecedented success of microtubule targeting agents such as paclitaxel in cancer chemotherapy, overexpression of P-glycoprotein (Pgp) and/or βIII-tubulin can cause clinical resistance to these agents. This limits their utility as cancer chemotherapeutic agents. In addition, several antitubulin agents, particularly the taxoids, have poor water solubility, so that their administration requires formulations that generate hypersensitivity reactions. Recently, we reported two analogs based on 2,6-dimethylcyclopenta[d]pyrimidine and pyrrolo[2,3-d]pyrimidine scaffolds that circumvent both these drawbacks. To study the structure-activity relationship of these new antimitotic agents, we have designed furo[2,3-d]pyrimidines as isosteres of pyrrolo[2,3-d]pyrimidines. We synthesized 2-methyl- and 2-desmethylfuro[2,3-d]pyrimidines AG1 and AG16 from the corresponding 4-chloro and 4-amino analogs, respectively, by treatment with N-methyl-4-methoxyaniline or with 4-methoxyiodobenzene followed by N4-methylation. The synthesis of the 4-chloro analog involved the reaction between acetamidine chloride and diethyl 2-(prop-2-ynyl)malonate in the presence of sodium metal, followed by base-catalyzed cyclization and chlorination. The 4-amino analog was synthesized by treating 1-hydroxypropan-2-one with malononitrile followed by cyclization using formamidine. The compounds AG1 and AG16 inhibit the growth of all the tumor cells in the NCI 60-cell panel with two-digit nanomolar GI50 values and also depolymerize cellular microtubules at low nanomolar concentrations. These compounds inhibit the assembly of purified tubulin (AG1, IC50 = 1.9 ± 0.1 µM; AG16, IC50 = 3.3 ± 0.5 µM) and the binding of colchicine to tubulin (AG1, 63% inhibition at 1 µM, 86% at 5 µM; AG16, 71% at 1 µM, 96% at 5 µM). These compounds are fully active in tumor cells overexpressing either Pgp or βIII-tubulin, thus overcoming two important mechanisms associated with tumor resistance to paclitaxel. We have thus identified a potentially important new scaffold, the furo[2,3-d]pyrimidine, for antitubulin agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3244. doi:10.1158/1538-7445.AM2011-3244