The matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases involved in the degrdn. of the major components of extracellular matrix. Some of them, namely MMP-2 and -9, are assocd. to tumor invasion and angiogenesis in several neoplasias. With the purpose of controlling the deregulated expression of these enzymes, several synthetic inhibitors were developed in the last years. Aimed at increasing the specific inhibitory activity for cancer-related MMPs, a set of N-derivs. of iminodiaceto-hydroxamic acids was developed, bioassayed towards the MMP-2 and -7 inhibition, and studied in soln. to evaluate the coordination modes to zinc(II) in equil. conditions. The results of the authors' studies on a series of iminodiaceto-hydroxamic acids contg. N-arylsulfonyl or N-arylmethyl moieties indicated that, although the sulfamoyl group is not involved in the zinc-coordination, the sulfonamide-contg. compds. are much more active than the amine analogs, due to favorable extra-functional interactions between the sulfonyl groups and amino-acid residues at the active site of the enzyme. Moreover, the inhibitory activity (nanomolar range) and the selectivity for MMP-2 can be achieved by inserting adequate arom. substituents on the inhibitor scaffold.
Iminodiacetyl-monohydroxamate derivatives as potent and selective MMP inhibitors
ROSSELLO, ARMANDO;TUCCINARDI, TIZIANO;
2006-01-01
Abstract
The matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases involved in the degrdn. of the major components of extracellular matrix. Some of them, namely MMP-2 and -9, are assocd. to tumor invasion and angiogenesis in several neoplasias. With the purpose of controlling the deregulated expression of these enzymes, several synthetic inhibitors were developed in the last years. Aimed at increasing the specific inhibitory activity for cancer-related MMPs, a set of N-derivs. of iminodiaceto-hydroxamic acids was developed, bioassayed towards the MMP-2 and -7 inhibition, and studied in soln. to evaluate the coordination modes to zinc(II) in equil. conditions. The results of the authors' studies on a series of iminodiaceto-hydroxamic acids contg. N-arylsulfonyl or N-arylmethyl moieties indicated that, although the sulfamoyl group is not involved in the zinc-coordination, the sulfonamide-contg. compds. are much more active than the amine analogs, due to favorable extra-functional interactions between the sulfonyl groups and amino-acid residues at the active site of the enzyme. Moreover, the inhibitory activity (nanomolar range) and the selectivity for MMP-2 can be achieved by inserting adequate arom. substituents on the inhibitor scaffold.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
