The Synthesis And Preliminary Activity Assay In Vitro Of Malic Acid Derivatives As Matrix Metalloproteinase Inhibitors

Matrix metalloproteinases (MMPs) belongs to a family of structurally related zinc-containing enzymes which usually come from fiber mother cells, neutrophils. macrophages and tumor cells. MMPs can remove large molecules such as collagen molecule, gelatin molecule; degradate collagen protein and proteoglycan, so as to providing space for the growth of new cells. Mmps is a kind of highly conservative enzymes in the evolution of natural, it widely distributed in plants, vertebrates and invertebrates, is the necessary enzyme during degradation of extracellullamatrix (ECM), almost all the ingredients of ECM. The expression of MMPs in tissue is very little in normal state, but it expression significant increase in the stimulate of inflammatory cells, hormone, growth factor and the conversion process of cells. This process involves the body of physiology and pathology, such as inflammation, embryogenesis, vessels, and the metastatic of tumor, etc. The MMPs, which have been proved to play key roles in the processes of tumor growth, invasion, metastasis and angiogenesis, are frequently overexpressed in malignant tumors, and are associated with an aggressive malignant phenotype and poor prognosis in patients with cancer.Therefore, the occurrence, development and transfer of cancer could be effectively control if the activity of MMPs could be restrict. All these findings make this enzyme an interesting target for possible anti-tumor drugs research recently year.In this thesis, based on the structure of MMPs, we design and synthesize 19 novel matrix metalloproteinases inhibitors (MMPIs). By analysis and summary the structural features of MMPIs which have been synthesized.The requirement for a molecule to be an effective inhibitor of the MMPIs is a functional group (e.g., carboxylic acid, hydroxamic acid, and sulfhydryl, etc.) capable of chelating the active-site zinc ion, one functional group at least which provides a hydrogen bond interaction with the enzyme backbone, and one or more side chains which undergo effective vander Waals interactions with the enzyme subsites.2-amino-1,3,4-thiadiazole derivatives have widely biological activity, many anti-cancer tests showed that they had good effects against cancer, is an important kind intermediates in the preparation of drug. Based on the above theory, we design and synthesize a series of compounds contain 2-amino-1,3,4-thiadiazole derivatives. Their structures are confirmed by IR, ESI-MS and 1H NMR, all the compounds are novel without reported except 6a and Al, B1, B3, D2 and D4. Preliminary bioactivity assays are carried out in vitro and have attained the data of their antitumor activity to K562.