Carbonic Anhydrases: Off Targets, Add‐On Activities, or Emerging Novel Targets?

Carbonic anhydrase inhibitors: Synthesis and inhibition of the cytosolic mammalian carbonic anhydrase isoforms I, II and VII with benzene sulfonamides incorporating 4,5,6,7-tetrachlorophthalimide moiety

“…The weak inhibition of this isoform may be considered a positive feature of this class of CAIs since hCA I, highly abundant in red blood cells, is undoubtedly an offtarget when considering other applications of the CAIs. 26 ii. The physiologically dominant cytosolic isoform hCA II was generally strongly inhibited by the synthesized sulfonamide, which showed K is in the range of 2.4-4515 nM (Table 3).…”

“…Overall, these sulfonamides showed a good inhibitory action towards hCA II, except for the orthanilamide derivative 5 which was a weak inhibitor 26. …”

Synthesis and inhibition potency of novel ureido benzenesulfonamides incorporating GABA as tumor-associated carbonic anhydrase IX and XII inhibitors

“…On the other hand, the remaining substitution patterns R led to compounds with inhibition constants of the same order of magnitude as the clinically used drug acetazolamide, AAZ, 5-acetamido-1,3,4-thiadiazole-2-sulfonamide ( Table 2). The low inhibition of this isoform may be considered as a positive characteristic of this new series of compounds (shared also with the corresponding 4-substituted-ureido-benzenesulfonamide derivatives A, C and D reported earlier) 21 since the ubiquitous isoform hCA I is abundant in red blood cells, it can be certainly considered an important off-target when research of antitumor CAIs is involved 24 .…”

“…Only recently it has been developed several novel generations of sulfonamide CAIs, which posses a remarkable selectivity profile for inhibiting prevalently the two transmembrane hCA IX and XII isoforms [17][18][19][20]24 . Among such isoform-selective benzenesulfonamide CAIs, the ureido-containing inhibitors are very interesting, as some representatives of this class (among which compounds A-D) possessed nanomolar activity for the inhibition of the tumor-associated isoforms hCA IX and XII; whereas they were much weaker inhibitors of the widespread, cytosolic off-target isoforms hCA I and II 21 .…”

Polypharmacology of sulfonamides: pazopanib, a multitargeted receptor tyrosine kinase inhibitor in clinical use, potently inhibits several mammalian carbonic anhydrases

“…33 Indeed, recent examples of drugs, which in addition to the targets for which they have been originally designed, also inhibit CAs, are the antiepileptic zonisamide, the sulfonamide coxibs (celecoxib, valdecoxib and apricoxib), as well as several primary sulfamates (topiramate, irosustat), which incorporate a group very similar to the sulfonamide one, and which exert their pharmacological action also due to the potent inhibition of some isoforms of this enzyme. 33 Our data presented here for pazopanib 2 point out that this clinically used drug, designed as an inhibitor of PTKs such as VEGFR, PDGFR and c-Kit, and which shows a significant antitumor effect, is also a very strong inhibitor of several CA isoforms, among which two are involved in tumorigenesis, CA IX and XII. Indeed, pazopanib inhibits these enzymes with K I s of 9.1 nM against hCA IX and 0.88 nM against hCA XII, which means that at therapeutic concentrations the compound will inhibit these tumor-associated enzymes.…”