Dual inhibitors of matrix metalloproteinases and carbonic anhydrases: iminodiacetyl-based hydroxamate-benzenesulfonamide conjugates.
Matrix metalloproteinases (MMPs) and carbonic anhydrases (CAs) are two classes of zinc enzymes with different roles and catalytic targets, such as the degradation of most of the extracellular matrix (ECM) proteins and the regulation of the CO(2)/HCO(3)(-) equilibrium in the cells, respectively. Both families have isoforms which were proved to be involved in several stages of carcinogenic processes, and so the selective inhibition of these enzymes might be of interest in cancer therapy. We report herein the design, synthesis, and in vitro evaluation of a series of compounds possessing the iminodiacetic acid as the main backbone and two functional groups attached, namely, the hydroxamic acid and the arylsulfonamide (ArSO(2)NH(2)) moieties, to enable the inhibition of MMPs and CAs, respectively. These compounds were demonstrated to strongly inhibit both MMPs and CAs, some of them from the nanomolar to subnanomolar range. Furthermore, a docking study for MMPs was reported for the most promising compound in order to investigate its binding interactions with the different MMPs.
Marques
Sérgio M
SM
Centro de Química Estrutural, Instituto Superior Técnico, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal.
Nuti
Elisa
E
Rossello
Armando
A
Supuran
Claudiu T
CT
Tuccinardi
Tiziano
T
Martinelli
Adriano
A
Santos
M Amélia
MA
D002256:Carbonic Anhydrases / Q000378:metabolism*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry*; D000860:Hypoxia; D020128:Inhibitory Concentration 50; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008956:Models, Chemical; D008968:Molecular Conformation; D011485:Protein Binding; D020033:Protein Isoforms; D013449:Sulfonamides / Q000737:chemistry*; D015032:Zinc / Q000737:chemistry; D000096926:Benzenesulfonamides
D002256:Carbonic Anhydrases; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D020782:Matrix Metalloproteinases; D020033:Protein Isoforms; D013449:Sulfonamides; D015032:Zinc; D000096926:Benzenesulfonamides