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

Matrix metalloproteinase (matrix metalloproteinases, MMPs) are a large catalytically active metals depend on the zinc ion proteolytic enzyme. Under physiological conditions, MMPs are present by the form of zymogen. However, if there are specific external stimulus such as growth factors and cytokines in vivo, the overexpression of MMPs will occurs. The excessive activation of MMPs then will cause the degradation of the extracellular matrix (extracellular matrix, ECM) due to the degradation of the basement membrane by MMPs, and proliferation and malignant tumors also occur. Moreover, rheumatoid arthritis, angiogenesis, periodontal disease and a number of tumor diffusion transfer is closely related to the MMPs.Structure of physiological function and MMP-7is described. So far there are more than20kinds of the MMPs have been discovered, only the MMP-1, MMP-2and MMP-7is an effective target enzymes to research anti-cancer drugs. Wherein, MMP-7has been determined to be secreted by the tumor cells, which can induce tumor cells to be cancer cells. MMP-7is found in pancreatic cancer, lung cancer, colon cancer, prostate cancer, liver cancer and other cancers as over expression. Therefore, design and development of an effective inhibitor against MMP-7in the fight against the proliferation of cancer cells, proliferation and transfer of drugs has broad prospects.Based on the known inhibitors against MMP-7and three-dimensional structure of the binding mode of MMP-7, the paper designed two-isobutyl-3-hydroxy-butyrylcholinesterase-(S)-tert-leucine as backbond. Our group adopt a new type of zinc binding group, nitro group, to be the zinc binding group (zinc-binding group, ZBG) to synthesize a series of compounds.Towards target compound26A,26B,26C,26D the determination of inhibitory effect has been achieved.The result indicates that26A,26B,26C,26D show excellent inhibitory effect against MMP-7.The value of Ki is165.57nM,55.93nM,98.47nM,83.33nM respectablely, exhibiting relevant good result compared with the inhibitor against MMP-7in the literature.