Synthesis And Kinetics Evaluation Of Nitro Derivates As Selective Inhibitor Against Matrix Metalloproteinase-7

Matrix metalloproteinases (MMP) is a large class of endopeptidase within zinc. MMP exists usually in the form of plasminogen. When the specific stimuli exists, such as growth factor stimulation and cytokines, in vivo overexpression or overactivation of MMP occur, leading to the level of extracellular matrix (ECM) disorders, so causing a variety of diseases, such as skin cancer, cardiovascular disease, multiple sclerosis, osteoarthritis, neutral neurological diseases, rheumatoid arthritis and so on.Among the more than 20 kinds of MMP currently found, MMP-1, MMP-2 and MMP-7 is considered to be effective anti-cancer drugs target enzymes. Whhile secreted by the tumor cells, MMP-7 can induce the evolution from tumor cells into cancer cells. The over-expression of MMP-7 were found in pancreatic cancer, lung cancer, colon cancer, prostate cancer, liver cancer and other malignant tumors. Therefore, design and development of an effective selective inhibitor against MMP-7 in the fight against proliferation of cancer cells, proliferation and metastasis of drugs has broad prospects.According to the strategy of general selective inhibitor of MMP, this paper chooses (2R)-2-isobutyl-3-nitro-propionic acid-(S)-tert-leucine as a basic skeleton, introducing nitro group as the zinc binding group, designed and synthesized a series of nitro compounds to explore their selective capability against MMP-7.Kinetic results show that the four target compounds showed a good inhibitory effect against MMP-7, the Ki values are 21.4 nM,15.5 nM,15.3 nM,17.3 nM. It’s ideal result compared to the MMP-7 inhibitors reported in the literature. To the selective capability, compound (2R)-2-isobutyl-3-nitro-propionic acid-(S)-tert-leucyl 3-trifluoromethyl-benzylamine (4c) significantly improved selectivity.Further molecular docking experiments showed that two oxygen atoms of the nitro chelate the catalytic Zn2+, R-type isobutyl interacts the S1’ pocket of MMP-7, S-type t-butyl interacts the S21 pocket of MMP-7, the terminal 3-trifluoromethylbenzylamine interacts the S31 pocket of MMP-7, and compound 4c forms four hydrogen bonds with the active site of MMP-7.