Carbonic anhydrase and matrix metalloproteinase inhibitors. Inhibition of human tumor-associated isozymes IX and cytosolic isozyme I and II with sulfonylated hydroxamates.
A series of sulfonylated hydroxamates were synthesized and evaluated as dual inhibitors of both human carbonic anhydrases (hCAs) and matrix metalloproteinases (MMPs), two metalloenzyme families involved in carcinogenesis and tumor invasion processes. The new derivatives were tested on three CA isozymes, the cytosolic isozymes I and II, and the transmembrane, tumor-associated isozyme IX, and also on human gelatinases (MMP-2 and MMP-9). Some of the new derivatives proved to be potent and selective inhibitors of CA II, but only compounds 3b and 6b, devoid of the arylsulfonyl moiety, proved to have a better inhibitory activity on hCA IX than on hCA I and II, in the micromolar range.
Nuti
Elisa
E
Dipartimento di Scienze Farmaceutiche, Università di Pisa, via Bonanno 6, 56126 Pisa, Italy.
Orlandini
Elisabetta
E
Nencetti
Susanna
S
Rossello
Armando
A
Innocenti
Alessio
A
Scozzafava
Andrea
A
Supuran
Claudiu T
CT
D000818:Animals; D024401:Carbonic Anhydrase I / Q000037:antagonists & inhibitors*; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors*; D003600:Cytosol / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007527:Isoenzymes; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D015394:Molecular Structure; D009101:Multiple Myeloma / Q000188:drug therapy / Q000473:pathology; D013329:Structure-Activity Relationship; D013451:Sulfonic Acids / Q000737:chemistry*; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D007527:Isoenzymes; D061965:Matrix Metalloproteinase Inhibitors; D013451:Sulfonic Acids; D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II