Synthetic MMP Inhibitors: Slow-Binding Behaviour of Enantioselective N-O-Sulfonamido Based Inhibitors Directed to Specific Matrixins

The kinetic behavior of some newly synthesized hydroxamate inhibitors on the matrixins MMP2 and MMP13 was evaluated. Our enantiomeric N-O-alkylsulfonamido-based MMP inhibitors (R)-EN73 and (S)-EN73, which show IC50 values in the nanomolar range on these matrixins, were found to display slow-binding kinetics. On the contrary, their achiral analogs devoid of the P1 substituent, such as CC27, or other model inhibitors bearing different substituents in P2' as the N-alkylsulfonamido-based SM3 or the N-H sulfonamido-based FO8, displayed a kinetic behavior consistent with a rapid equil. interaction with these enzymes. This behavior, however, was not obsd. when the same enantiomeric compds. were tested on a different matrixin, e.g., MMP-1, that shows a far higher IC50 value for these inhibitors. Considering shape and size differences of the S1' pocket of these matrixins, we carried on this kinetic characterization also on P1' small arom. substituted inhibitors belonging to these sulfonylated ligands. An enlarged and compared anal. regarding the potency and selectivity of these inhibitors, against some target and antitarget MMPs involved in cancer and arthritic diseases, was developed.