Carbonic anhydrase activators - part 21. Novel activators of isozymes I, II and IV incorporating carboxamido and ureido histamine moieties.
Reaction of histamine 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. Carboxamido derivatives were obtained by reaction of the key intermediate with carboxylic acid anhydrides, acyl chlorides or carboxylic acids in the presence of carbodiimides. Reaction of the same key intermediate with isocyanates, isothiocyanates, cyanamide or dicyandiamide afforded another series of compounds. Deprotection of the above-mentioned intermediates with hydrochloric acid in dioxane afforded two series of compounds, histamine derivatives possessing carboxamido, ureido, thioureido or guanidino moieties in their molecule. 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, h = human, b = bovine isozyme). 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 10-25 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.
Scozzafava
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Università degli Studi, Laboratorio di Chimica Inorganica e Bioinorganica, Via Gino Capponi 7, I-50121, Florence, Italy.
Supuran
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D000818:Animals; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000378:metabolism*; D002264:Carboxylic Acids; D002417:Cattle; D018360:Crystallography, X-Ray; D004789:Enzyme Activation / Q000187:drug effects*; D020536:Enzyme Activators / Q000138:chemical synthesis* / Q000494:pharmacology; D006632:Histamine / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D017953:Isocyanates; D007527:Isoenzymes / Q000378:metabolism*; D017879:Isothiocyanates; D011994:Recombinant Proteins / Q000378:metabolism
D002264:Carboxylic Acids; D020536:Enzyme Activators; D017953:Isocyanates; D007527:Isoenzymes; D017879:Isothiocyanates; D011994:Recombinant Proteins; C037152:isothiocyanic acid; D006632:Histamine; D002256:Carbonic Anhydrases