Carbonic Anhydrase Activators: Synthesis of High Affinity Isozymes I, II and IV Activators, Derivatives of 4-(4-Tosylureido-Amino Acyl)Ethyl-1 H -Imidazole (Histamine Derivatives)

Andrea Scozzafava (1) , Bogdan Iorga (2) , Claudiu T. Supuran (1)

1 LCBI-UniFI - Laboratorio di Chimica Bioinorganica [UniFI, Firenze] = Laboratory of Bioinorganic Chemistry [UniFI Florence]
2 University of Bucharest, Faculty of Chemistry, Department of Organic Chemistry, Biochemistry and Catalysis

Reaction of histamine (Hst) with tetrabromophthalic anhydride and protection of its imidazole moiety with tritylsulfeiiyl 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 4-tosylureido amino acids/dipeptides (ts-AA) in the presence of carbodiimides, afforded after deprotection of the imidazole moiety, a series of compounds with the general formula ts-AA-Hst (ts = 4-MeC6H,SO2NHCO). Some structurally related dipeptide derivatives with the general formula ts-AAl-AA2-Hst, were also prepared, by in a similar way to the amino acyl compounds mentioned above. The new derivatives were examined as activators of three carbonic anhydrase (CA) isozymes, hCA I, hCA I1 (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 1-10 nanomolar range for the best compounds. hCA I1 was on the other hand activatable with affinities around 20-50nM. 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.

Mots clés: Carbonic anhydrase; Histamine; Amino acid; Dipeptide; Tosyl isocyanate; Tosylurea; Enzyme activators; Proton shuttling *See Ref. [I]

Domaines: Chimie

Andrea Scozzafava, Bogdan Iorga, Claudiu T. Supuran. Carbonic Anhydrase Activators: Synthesis of High Affinity Isozymes I, II and IV Activators, Derivatives of 4-(4-Tosylureido-Amino Acyl)Ethyl-1 H -Imidazole (Histamine Derivatives). Journal of Enzyme Inhibition and Medicinal Chemistry, 2000, 15 (2), pp.139-161. ⟨10.1080/14756360009030347⟩. ⟨hal-03161496⟩