SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF GELATINASE INHIBITORS DERIVED FROM MATLYSTATINS

To investigate a series of new inhibitors of gelatinases based on matlystatin B (Ib), extensive structure-activity relationship studies were performed. The new derivatives were evaluated in vitro for the ability to inhibit gelatinases, The inhibitory activities against thermolysin were also assayed to test the compounds' selectivity, Among the compounds modified at the P-3' moiety, the N-methylamide derivative 5 g was virtually twice as effective on gelatinase B as the parent compound Ib (5 g, IC50 = 0.27 mu M vs, 1b, IC50 = 0.57 mu M). Other derivatives, including 1) esters 7a and 7b having the ester portions P-2' and P-3', 2) the cyclic amino acids, L-proline or L-pipecolinic acid (13a and 13b) bearing P-2', and 3) compounds 29a and 29b representing an attachment of the pentyl side chain at C3' (P-1' side chain) instead of C2', all showed decreased potencies, The key discovery was the observation that the introduction of a nonyl group at the P-1' position yielded a compound (31f, IC50 = 0.0012 mu M) with high inhibitory activity against gelatinases and high selectivity over thermolysin. This result suggested that the S-1' subsites of the gelatinases have a locally deep hydrophobic structure, since on the basis of the optimum inhibitory activity in the alkyl series, the nonyl group seems to fit best into this hydrophobic pocket, Thus 31f exhibited a 475-fold more potent inhibitory activity than Ib towards gelatinase B.