Glycosyl Isoxazoles for Targeting of Tumor Microenvironment and Cancer Cells: Highly Selective Inhibitors of Carbonic Anhydrases IX and XII Showing Cytotoxic Activity

Abstract

We report the synthesis of twelve novel O-glycosylmethyl isoxazoles incorporating the phenoxyaryl moiety, that were designed to selectively target the cancer-related human carbonic anhydrase (CA, EC 4.2.1.1) isoforms. The O-glycosides have been prepared by cycloaddition of nitrile oxides to O-propargyl glycosides. Compounds were assessed as inhibitors of the physiologically dominant isozymes hCA I and II and the tumor-associated isozyme hCA IX and hCA XII. In this study, several glycosides have been identified as highly selective inhibitors of hCA IX and XII. Glycoconjugation enhances the anticancer activity against human osteosarcoma cell line. Thus, these glycosides may prove interesting lead candidates for a targeted cancer therapy.