title: Carbonic anhydrase activators: amino acyl/dipeptidyl histamine derivatives bind with high affinity to isozymes I, II and IV and act as efficient activators.
abstract: Reaction of histamine (Hst) with tetrabromophthalic anhydride and protection of its imidazole moiety with tritylsulfenyl chloride, followed by hydrazinolysis, afforded N-1-tritylsulfenyl-histamine, a key intermediate which was further derivatized at its aminoethyl moiety. Reaction of the key intermediate with N-Boc-amino acids/dipeptides (Boc-AA) in the presence of carbodiimides afforded, after deprotection of the imidazolic and amino moieties, a series of compounds with the general formula AA-Hst (AA = amino acyl; dipeptidyl). The new derivatives were assayed as activators of three carbonic anhydrase (CA) isozymes, hCA I, hCA II (cytosolic forms) and bCA IV (membrane-bound form). Efficient activation was observed against all three isozymes, but especially against hCA I and bCA IV, with affinities in the nanomolar range for the best compounds. hCA II was, on the other hand, activatable with affinities around 10-20 nM. This new class of CA activators might lead to the development of drugs/diagnostic agents for the CA deficiency syndrome, a genetic disease of bone, brain and kidneys.
authors.affiliation: Universitá degli Studi, Laboratorio di Chimica Inorganica e Bioinorganica, Florence, Italy. cts@bio.chim.unifi.it
authors.forename: C T
authors.initials: CT
authors.lastname: Supuran
authors.forename: A
authors.initials: A
authors.lastname: Scozzafava
mesh_terms: D000818:Animals; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D002417:Cattle; D004789:Enzyme Activation / Q000187:drug effects; D006632:Histamine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008661:Metabolism, Inborn Errors / Q000201:enzymology; D008958:Models, Molecular; D011487:Protein Conformation; D013577:Syndrome
chemical_list: D008024:Ligands; D006632:Histamine; D002256:Carbonic Anhydrases