Synthesis and evaluation of new tripeptide phosphonate inhibitors of MMP-8 and MMP-2

The phosphotryptophan derivative L-Pro-L-Leu-L-(P)Trp(OH)2 (2b) was reported as the first example of left-hand-side1 phosphonate inhibitor of MMP-8. Its uncommon mode of binding to MMP-8 was mainly ascribed to the presence of the proline residue in P3. Ten new analogues of 2b were obtained by replacement of the aminoterminal L-Pro with aminoacid residues bearing small side chains. Most of the new analogues show an increase of affinity for MMP-2 and MMP-8, and different profiles of selectivity. Computer simulations were performed to explain the effects of substitutions on the preferred mode of binding. They reveal that most of the new analogues are probably accommodated in the right, rather than left-hand side of MMP-8 active site.