Cyclic tertiary sulfamates: Selective inhibition of the tumor-associated carbonic anhydrases IX and XII by N- and O-substituted acesulfame derivatives

•hCA IX and hCA XII enzymes are over-expressed in several hypoxic tumors.•N- and O-alkylated acesulfame derivatives were tested against hCA I, II, IX and XII.•Many derivatives selectively inhibited the cancer-related hCA IX and/or hCA XII.•These derivatives could give new insights into anticancer therapy.

Carbonic anhydrase (hCA) IX and XII isoforms are over-expressed both in primary and in metastatic cell lines of hypoxic tumors and are innovative targets for cancer diagnosis and treatment. On the basis of the importance of the pharmacophoric sulfamate moiety (bioisostere of the sulfonamide group) present in the structure of recent human CA inhibitors, we designed N-alkylated and O-alkylated derivatives of acesulfame, a cyclic tertiary sulfamate, assessing the inhibitory activity against the ubiquitous isoforms hCA I and II and the cancer-related isoforms hCA IX and XII. All derivatives were nanomolar inhibitors, with some of them possessing an outstanding selectivity towards the tumor-associated hCA IX and/or hCA XII isoforms.

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