Abstract 1367: Substituted Pyrimido[4,5-b]indoles with single agent combination chemotherapeutic potential

Abstract

Abstract Combinations of cytotoxic agents with antiangiogenic agents have shown significant promise in cancer treatment, and several such clinical trials are currently underway. We previously identified two compounds with a 5-(thioaryl)-9H-pyrimido[4,5-b]indole-2,4-diamine scaffold that each inhibit vascular endothelial growth factor receptor-2 (VEGFR-2) and platelet derived growth factor receptor-beta (PDGFR-β) for antiangiogenic effects and remarkably also inhibit human thymidylate synthase (hTS) for cytotoxic effects. In a COLO-205 xenograft mouse model one of these analogs demonstrated potent tumor growth inhibition, inhibition of metastasis, and antiangiogenic effects in vivo. Thus, these compounds afford combination chemotherapeutic potential in single agents. In an effort to optimize the structural requirements for antiangiogenic effects and hTS inhibition, six additional compounds were synthesized. Electron withdrawing (3,4-diClPh, 4-ClPh), electron donating (2,5-diOMePh, 4-OMePh) and bulky (1-naphthyl, 2-naphthyl) thioaryl groups in the 5-(thioaryl)-9H-pyrimido[4,5-b]indole-2,4-diamine scaffold were selected to establish optimum activity. The synthesis of these compounds involved the nucleophilic displacement of the common intermediate 5-bromo-9H-pyrimido[4,5-b]indole-2,4-diamine with appropriate benzenethiols. A novel four step synthetic scheme to the common intermediate was developed which is more efficient relative to the previously reported six step synthesis. Biological evaluation of these compounds in various RTKs indicated that in the VEGFR-2 assay the 2,5-diOMePh substituted compound was equipotent to the standard SU5416 used in this assay. In the hTS assay, the 2-naphthyl, 4-OMePh, and 4-ClPh substituted compounds were nanomolar inhibitors and were 3-fold better than or equipotent to the standard TS inhibitor raltitrexed. 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 1367. doi:10.1158/1538-7445.AM2011-1367