Inhibition of carbonic anhydrase isozymes I, II and IX with benzenesulfonamides containing an organometallic moiety.
A novel series of benzenesulfonamides that contain ferrocenyl or ruthenocenyl moieties were synthesized and investigated for their ability to inhibit the enzymatic activity of physiologically relevant carbonic anhydrase (CA) isozymes: hCA I, II and tumour-associated IX (h=human). This manuscript describes the regioselective synthesis of both the 1,4- and 1,5-disubstituted-1,2,3-triazole benzenesulfonamides from ethynylmetallocene substrates. This is the first report describing the covalent attachment of organometallic moieties to the arylsulfonamide (ArSO(2)NH(2)) CA recognition pharmacophore. At hCA I these metallocene derivatives were either nanomolar or low micromolar inhibitors, while against hCA II and IX inhibition in the range of 9.7-80nM and 10.3-85nM, respectively, was observed. The ruthenocenyl derivatives gave superior CA inhibition compared to the ferrocenyl compounds across all three CA isozymes. These compounds constitute a new organometallic class of CA inhibitors with promising biological activity.
Salmon
Adam J
AJ
Eskitis Institute for Cell and Molecular Therapies, Griffith University, Nathan, Qld 4111, Australia.
Williams
Michael L
ML
Innocenti
Alessio
A
Vullo
Daniela
D
Supuran
Claudiu T
CT
Poulsen
Sally-Ann
SA
D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000187:drug effects*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D009682:Magnetic Resonance Spectroscopy; D009942:Organometallic Compounds / Q000494:pharmacology*; D013379:Substrate Specificity; D013449:Sulfonamides / Q000494:pharmacology*
D002257:Carbonic Anhydrase Inhibitors; D007527:Isoenzymes; D009942:Organometallic Compounds; D013449:Sulfonamides; D002256:Carbonic Anhydrases