Nitro-based Pseudo-dipeptide Compounds As Selective Inhibitors Against Matrix Metalloproteinase-7

Matrix metalloproteinases (matrix metalloproteinases, MMPs) are a large class of zinc-dependent proteolytic enzymes. MMP-7, featured by the smallest domain of MMP, is actually secreted by the tumor cells, which could induce the development to cancer. Over-expression and/or over-activation of MMP-7 were found in various malignant tumors including lung cancer, liver cancer, breast cancer, pancreatic cancer and others. Therefore, the development of effective selective inhibitor of MMP-7 has broad prospects for the treatment of cancer.Because both MMP-1 and MMP-7 have the similar Si’hydrophobic pocket, it remains to be a challenge to fulfill MMP-7 selective inhibitors over MMP-1 up to now. In the presented paper, a series of nitro-based dipeptidic compounds were designed and synthesized as MMP inhibitors, which optimize the side chain to enhance the effect of selective inhibitors of MMP-7.Firstly, three compounds, (2R)-2-iso-butyl-3-nitro-propionyl-(S)-phenylalanyl-3-trifluoromethyl benzyl amine, (2R)-2-iso-butyl-3-nitro-propionyl-(S)-tyrosyl-3-trifluoromethyl benzyl amine, (2R)-2-iso-butyl-3-nitro-propionyl-(S)-aspartyl-3-trifluoromethyl benzylamine have been designed and synthesized, which aimed to explore the effects of the structure of the P2’ side chains on inhibitory potency and selectivity for MMP-7. Kinetic assays disclose that the inhibition constants of MMP-7 were 4.1 μM,4.4 μM, and 1.6 μM, respectively. The values of Ki(MMP-7/MMP-1), defined as the selectivity, were 4.9,9.3, and 10.6, respectively. The result indicates that optimization of P2 ’side chains could improve the inhibitory activity against three MMPs in screen, but loss of the selectivity is also observed. Molecular docking results revealed that nitro group coordinate to the catalytic zinc with the bidentate form, while the number of hydrogen bonds between the residues on MMP and inhibitors skeleton determines the inhibitory activities of the inhibitor.On the basis of this structure-activity relationships,3,4-dimethoxy-(R)-dopa methyl was introduced as the P3’ side chain with keeping the t-Bu as the P3’ side chain. (2R)-2-iso-butyl-3-nitro-propionyl-(S)-tert-leucyl-3,4-dimethoxy-(R)-dopa was thus synthesized and evaluated as MMP inhibitors. Kinetic results indicate that the compound is by far the best selective inhibitor of MMP-7. The inhibitory constant is 0.45 μM, whiel the selectivity, Ki (MMP-7/MMP-1) is about 50.