The Design And Synthesis Of Inhibitors For Urokinase-type Plasminogen Activator And Enzyme Inhibitory Activity

The malignant tumor has evolved to become increasingly common and seriousthreat to the safety of human life, and it has become the second leading cause of deathin China and around the world. The occurrence and development of tumor is amμLti-step and mμLti-stage process, and the most important feature of malignanttumor from the benign tumor is the invasion and metastasis of biologicalcharacteristics. A large number of studies have found that urokinase plasminogenactivator(uPA) system (uPAS) is the originating links and performer to the tumorproliferation， invasion and metastasis-related signal pathway positive feedback, andit has been proved to be a very promising anticancer drugs target. The uPAS consistsof the serine protease uPA, its receptor uPAR, its two serpin inhibitors, plasminogenactivator inhibitor-1(PAI-1) and plasminogen activator inhibitor-2(PAI-2). The role ofanticancer drugs in uPAS has become a new hot spot of anticancer drugs research, andthe specific inhibitors of uPA is the earliest one of the research direction, which is themost in-depth study and obtained valuable resμLts.This thesis use upain-1as lead compounds, design and synthesis a series of novelcyclic peptide and peptidomimetic compounds, and then implement a preliminarystudy on the enzyme inhibition activity of the derivatization target product by use ofchromogenic substrate method. The thesis is divided into two parts. The first partmainly introduces the classification of uPA inhibitors and its research progress andadvantages and action mechanism of the uPA inhibitor, indicating the purpose andsignificance of this research project.The second part mainly introduces the design and synthesis of the uPA inhibitorsand their corresponding initial enzyme inhibition activity resμLts. Taking the cyclicpeptide uPA inhibitors upain-1cyclo[-CSWRGLENHRMC-] as lead compounds,10cyclic peptide compounds are designed and synthesized by the way of replacingpartial residue sites, combining solid phase and liquid phase synthesis method.Meanwhile,4peptide fragment of structure upain-1combined with uPA enzymecatalytic sites is taken as the leading compound to design and synthesize4simplifiedoligopeptide compounds.Using the chromogenic substrate method, amiloride as the positive control,14 target compound synthesized of the uPA enzyme were performed the uPA enzymeinhibitory activity in vitro screening with a single concentration (200μM). The resμLtsshowed that7cyclic peptide compounds. Then the IC50and Ki of these7compoundswere determined...