• MMP inhibitors

Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases, which degrade most of the extracellular matrix components. They play a central role in many physiological, as well as pathological processes, including carcinogenesis and tumour progression (such as MMP-2), this being the reason of interest of their inhibition.

Among the inhibitors already developed, a large number are sulfonylated compounds, namely containing arylsulfonyl moieties, and most of them bearing a hydroxamate as zinc-binding group (ZBG). However, this group has pharmacokinetic drawbacks, which has contributed to the in vivo inefficacy of these inhibitors as anticancer drugs.

Hence, we have developed new non-peptidic small molecules as MMP inhibitors, able to interact with the main sub-sites of the active centre of the enzymes. These new compounds have in common a benzothiazole (BTA) moiety, which is a known antitumour bioactive group, an arylsulfonyl group (ArSO2), and a ZBG to coordinate the zinc ion in the active site of the MMPs. The substituents were chosen based on molecular modelling studies. As ZBGs, the carboxylic, hydroxamic and hydrazide functional groups have been tested.

Potent MMP inhibitors (nM – μM range) containing BTA moiety were discovered and the activities found for the different ZBGs follow the order HA > Hyd > CA.

BTA moiety interacts favourably with MMP-2, mostly with aromatic and lipophilic residues moreover bulkier R1 substituents induce conformation distortion on the CA analogues, hindering the enzyme interaction; however, based on docking, such effect is not expected for the HAs.

Modeling studies also indicated that the BTA interaction may be improved by the nature and length of the BTA-sulfonamide spacer.

The preliminary results on inhibition of the tumour-related MMP-2, suggest the potential of these BTA-based compounds to play a role as anticancer agents.