Carbonic anhydrase inhibitors: an update on experimental agents for the treatment and imaging of hypoxic tumors

Benzenesulfonamides with different rigidity-conferring linkers as carbonic anhydrase inhibitors: an insight into the antiproliferative effect on glioblastoma, pancreatic, and breast cancer cells

“…Keeping in mind that the ureidic linker was successfully applied to the synthesis of potent CA IX and XII inhibitors, we followed a medicinal chemistry approach aimed at investigating how the cyclisation of this moiety into a rigidified imidazolidin-2-one group could impact CA inhibitory activity, isoform selectivity in vitro , and pharmacokinetic characteristics, considering the existing controversy in the field 33 , 37 . The introduction of the rigid imidazolidin-2-one linker was associated with a loss of selectivity for inhibiting CA IX and XII over CA II, but these compounds did possess interesting inhibition profiles.…”

The three-tails approach as a new strategy to improve selectivity of action of sulphonamide inhibitors against tumour-associated carbonic anhydrase IX and XII

“…In this first screening, mono-tailed ( 1–7 ) and three-tailed ( 18–50 ) compounds were analysed by a stopped-flow kinetic assay 41 with: the tumour-associated isoforms CA IV, IX, and XII and the main off-target isoforms CA I and II, if considered the anticancer application ( Table 1 ) 1 , 9–11 . The selectivity index of mono-tailed and three-tailed compounds vs. the off-target isoforms CA I and II are reported in Table S1 ( Supplementary Information ).…”

“…These proton export mechanisms, in concert with poor vascular drainage, are responsible to maintain an intracellular pH of 7.2–7.4, acidifying the extracellular pH to 6.2–6.8, which is strongly associated with the propagation, malignant progression, and resistance to chemotherapy and radiotherapy of tumours 1 , 2 , 6–11 . In detail, the CA IX and XII expression is strongly increased in many types of tumours 9 , 12–21 and is downregulated by the wild-type von Hippel–Lindau tumour suppressor protein (pVHL) 2 , 22 , 23 . In some cancer cells, the VHL gene is mutated leading to the strong upregulation of tumour-associated CA isoforms as a consequence of constitutive HIF activation 24 , 25 .…”

Targeting carbonic anhydrase IX and XII isoforms with small molecule inhibitors and monoclonal antibodies

“…This resulted in profound increase in inhibitory potential towards CAII, IX, and XII, however diminished its selectivity from tumor-associated isoforms towards the cytosolic ones. Drug design of the compounds based on SLC-0111 was extensively described by the aforementioned author and his group 123 , 126–129 .…”

“…These include the use of cytotoxins (monomethyl auristatin, tubulysin B, the maytansinoids, mertansine), antimalarial agents (artemisinin and dihydroartemisinin), EGFR antagonists, inhibitors of 15-lipoxygenase-cyclooxygenase 2, telomerase inhibitors, P-glycoprotein inhibitors, thioredoxin inhibitors, adenosine A2A receptor antagonists, pyrophosphatase/phosphodiesterase-3 inhibitors and others extensively reviewed by Supuran C.T. 126 , 212 …”