Study Of (2-isobutyl-3-nitro) Propionyl Amino Acids As The Inhibitors Against Thermolysin

Supramolecular chemistry is developed rapidly and applied widely in recent years as a new cross-disciplinary science. Zinc proteases are a family of enzymes having a catalytically essential zinc ion at their active sites. They are widely throughout found in a variety of tissues and play key roles in numerous physiological processes.The tissue inhibitors of metalloproteinases (TIMP) and the inhibitors of matrix metalloproteinases (MMP) can control the update of the extracellular matrix and maintain the cell stability. The effective MMP inhibitors can reduce the activity of MMP so that the above mechanism can be to balance.To get high selective MMP inhibitors, the exploitation and discovery of more potent and selective ZBGs is still required. A way to exploit the ZBG is built on the model of carboxypeptidase A (CPA) and thermolysin (TLN).We have introduced the TLN and TLN inhibitors. In this paper, we mainly discuss the synthesis of the peptide inhibitor with the nitro group as the combination group. With diethyl malonate as a raw material, we synthesize the final target compouds through nine-steps. The diastereomers are separated by column chromatography. The structures of the target compounds are characterized and the spatial configuration is determined by 2D H-H NOESY.The inhibitory activities against TLN were determined, and the structure-activity relationships were then established and discussed. The results of kinetics study indicate that the target compouds are good inhibitors against the TLN, and the values of Ki about S,S-NMPPA, S,R-NMPPA, S,S-MNMPPA and S,R-MNMPPA are respective 7.24μM,0.84μM,0.77μM and 83nM. Compare with the results, we can give some conclusions:the R configuration is fit for the S1' pocket of TLN and the size of the isobutyl is not only matched to theS1' pocket but also to the S2' pocket.