Dual inhibitors of matrix metalloproteinases and carbonic anhydrases: iminodiacetyl-based hydroxamate-benzenesulfonamide conjugates.

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Marques SM, Nuti E, Rossello A, Supuran CT, Tuccinardi T, Martinelli A, Santos MA

Dual inhibitors of matrix metalloproteinases and carbonic anhydrases: iminodiacetyl-based hydroxamate-benzenesulfonamide conjugates.

J Med Chem. 2008 Dec 25;51(24):7968-79. doi: 10.1021/jm800964f.

PubMed ID

19053764 [ View in PubMed

]

Abstract

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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Acetazolamide	Carbonic anhydrase 1	Ki (nM)	250	N/A	N/A	Details
Acetazolamide	Carbonic anhydrase 2	Ki (nM)	12	N/A	N/A	Details