Carbonic anhydrases (CAs, EC 4.2.1.1) are ubiquitous metalloenzymes found in numerous organisms across the tree of life, encoded by seven genetically distinct CA families: alfa-, beta-, gamma-, delta-, epsilon-, zeta- and teta-CAs . Carbonic anhydrases are metalloenzymes therefore they are catalytically effective only with one metal ion bound within the active site cavity, the apoenzymes being devoid of any catalytic activity.
In the last years, there has been evidence of the role that several CAs isoforms cover in tumorigenesis, as a result of the capability to create an acidic extracellular milieu useful for tumour survival, progression and adoption of metastatic phenotypes. The two transmembrane isoforms CAs IX and XII (tumor-related isoforms) are overexpressed in hypoxic tumors and have been linked to this behaviour, while showing a limited expression in normal tissues.In the light of the roles that hCA IX and XII have in the cancer malignancies, the development of inhibitor which selectively bind and inhibit these two enzymes could be useful in cancer treatment. Up to day, only few hCA IX and XII inhibitors endowed with good therapeutic profiles have been included in clinical trial (as Indisulam and SLC-0111). These outcomes suggest that there is a real possibility, as well as urgencies, to develop compounds able to increase the equipment to fight cancer. Compounds, based on saccharin and acesulfame scaffolds N-/O- substituted with different substituents, are endowed with low nanomolar inhibitory activity against hCA IX and XII, albeit some of them, retained activity against off-targets (hCA I and II). With the aim to ameliorate activity and selectivity towards the two tumor-related hCA isoforms, we will design and study a series of novel derivatives based on these scaffolds introducing various kinds of changes.
