Design, Synthesis, Activity Evaluatuion And Structure-Activity Relationship Of Matrix Metalloproteinase Inhibitors

Matrix Metalloproteinases (MMPs) constitute a family of zinc containing endopeptidase, which were found and studied recently possessing proteolytic potency of numerous proteins, such as gelatin, collagin and proteoglycin. As studied by cell biology and molecular biology, with the mechanism of normal physiological modulation, MMPs degrade almost all extracellular matrix (ECM) and participate a lot of physiological process, including tissue remodeling, pregnancy, wound healing. In recent pathological study, MMPs were found highly expressed in ECM associated with many diseases, such as inflammation and cancer, mainly arthritis, tumor invasion and metastasis. Thus MMPs have been developed to be another important target for treatment of arthritis and tumor invasion and metastasis, and MMPs inhibitors becomeexactly) necessary to be developed. Studies about MMPs, especially those of inhibitors have considerably progressed abroad, in which mainly two types of inhibitors were classified, including peptide mimics and non-peptide mimics,with the later more offoreground. Now a number of MMPs inhibitors have developed into clinical trial as candidates for antiarthritis and anticancer therapy.In this thesis,method of Computer Aided Drug Design (CADD) was taken, in which, combined with Docking calculation, Comparative Molecular Field Analysis (CoMFA) were applied in the three dimensional Quantitative Structure and Activity Relationship (3D-QSAR) study of known MMPs inhibitors. Thus pharmacophore models for inhibitors of MMP-1, MMP-2, MMP-3, MMP-9 were respectively founded with good correlation and prediction potency.In the aid of Unity4.3 program, two database, NCI (National Cancer Institute of US) and Maybridge, were searched with flexibility upon query set according to the results of CoMFA and information from activity caves of MMPs provided by X-ray crystallography study. Depending on the hits from Unity search, together with conclusion from 3D-QSAR and synthetic feasibility,γ-aryl butyl keto acid based structure were designed as the main skeleton, in which 2-arylcarbonyl-cyclohexane -carboxylic acid andγ-arylbutyl keto acid containing a-heteroatom and hydroxamic acid derivatives were included.89 target compounds were synthesized during which 168 compounds were obtained and 106 were unreported and structurally confirmed by NMR and MS. In theMMPs (MMP-1, MMP-2, MMP-3, MMP-9) inhibition assay, most compounds exhibited inhibition potency with different grade and selective inhibition at MMP-2.Structure and Activity Relationships were analyzed to provide valuable clues for structure design and optimization in the next step.