Design And Synthesis Of Matrix Metalloproteinases-2,9 Inhibitors Based On Computer-Aided Drug Design

The matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidase involved in the degradation and remodeling the extracellular matrix proteins. MMPs also play critical roles in many physiological processes, such as embryonic development, angiogenesis and wound healing. In normal physiological states, the activities of these enzymes are well regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs), which mediate the stability of cells all together. 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, MMPs have become attractive targets for anticancer drug design. Accordingly, research on inhibitors targeting at MMPs, especially which have high selectivity at gelatinase (MMP-2, 9), is a very promising strategy in the development of current anti-angiogenesis therapy of tumor.Based on the 3D structures of known MMPIs and binding modes of these compounds in complex with MMPs, we designed and synthesized a series of new pyrrolidines compounds with the aid of BioMedCache6.0 and Sybyl7.0 software. In first step, CoMFA study was carried out on the N1-acetyl substituted pyrolidines compounds which synthesized in our group. This result guided us designing the a series of new compounds which introducing different substitution group in pyrrolidines. Then target compounds were synthesized using 4-hydroxyproline as material through a reaction sequence including methylation, acetylation, S_N2...