Design And Synthesis Of MMP Inhibitor With A Purine Or Pyrimidine Backbone

Matrix metalloproteinases (MMPs) are a family of structurally relatedzinc metallproteinases that degrade and remodel structural proteins in theextracellular matrix. Under normal physiological conditions, the proteolyticactivities are closely controlled through expression as proenzymes thatrequire activation for activity, and also through direct inhibition of theenzymes by tissue inhibitors of metalloproteinases (TIMPs). MMPs wereshown to participate in a variety of physiological and pathological processes.Excessive MMPs activity has been implicated in numerous desease statesinvolving matrix degradation, which include arthritis, acncer, and perodontaldeseases. In view of their involvement in various diseases inhibition ofspecific MMPs may prove to be clinically effective in halting the advance ofthese diseases. Recently there has been a significant interest in developingMMP inhibitors that may control the aberrant activity of MMP production.In this thesis, the first chapter simply reviews MMPs and theinvestigation process of the inhibitors of MMPs .The review involves theclassification of MMPs, the study of the proteolytic activities of the MMPsand the participating in a variety of physiological and pathological processesof MMPs. In addition, the chapter also introduces the strategy anddevelopment of the synthetic MMPs inhibitors. The synthetic strategymethods include the based substrate design, based structure design andcombinatorial chemisty ect. At present the most applying method is basedstructure design. Among various of synthetic inhibitors several of them haveentered the clinical experiments phases. The promising inhibitors maybebecome new generation anti-arthritis and anti-cancer candidate drugs.Purine and pyrimidine derivatives are widely applied in biology andpharmaceutical chemistry. Presently some of derivatives have beendeveloped as anti-virus and anti-AIDS drugs. The second chapter of thisthesis details the design and sythesis process of novel MMP inhibitors basedpurine or pyrimidine scaffold. Finally, 2-alkylthio-4-arylsulfanilamide-pyrimidine-5-hydroxamates as a novel kind of MMP inhibitors wereobtained. All compouds were tested in vitro for the inhibition of MMP-16.The results indicates, in general, all of these compounds inhibit MMP-16 inmoderate degree with IC50 values ranging from 10uM to 26uM.