Abstract 668: Second generation silicon derivatives of indomethacin: Synthesis of potent COX-2 selective agents with improved anticancer activity

Abstract

Abstract Elevated tumor cyclooxygenase-2 is associated with poor overall survival in patients with a variety of cancers. Patients with elevated COX-2 that receive a COX-2 inhibitor have demonstrated improved survival. Indomethacin (IM) is a COX-non-selective inhibitor with demonstrated anticancer activity in patients. The anticancer effects of IM are related to inhibition of COX-2 as well as COX-independent targets. We now report the improved synthesis and activity of IM-sila- amide derivatives where strategic silicon addition results in COX-2 selective IM derivatives that demonstrate activity in mouse models of human cancers and are devoid of the COX-1 associated toxicities. The sila-IM compounds demonstrated improved inhibition of purified human COX-2, IC50 0.2 uM and limited inhibition of COX-1 up to 10 uM. Sila-IM derivatives were also found to be potent inhibitors of NF-κB transcription activating function at concentrations below 1.0 UM. A sila-IM derivative Silexsyn was tested in various animal models of human cancer following oral administration. Significant activity was observed in models of non-small cell lung cancer and pancreas cancer. Potent synergism was observed for Silexsyn in combination with EGFR inhibitors. A synthetic methodology incorporating a heteroatom in the amino-functional silane has been developed and used to generate second-generation sila-IM derivatives that could have improved pharmacological properties. The introduction of silicon into an approved scaffold represents an efficient strategy for the rapid production of biologically relevant therapeutics for the treatment of cancer. 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 668. doi:10.1158/1538-7445.AM2011-668