Study On Peptide Antineoplastic Drugs Targeting 20S Proteasome And Pharmacodynamic Evaluation Based On Micro PET Technology

ObJective:Ubiquitin-proteasome pathway?UPP?is one of the important pathways for selective degradation of proteins in vivo.These proteins include cyclin and cyclin-dependent kinase?CDK?,tumor suppressor protein p53,cytokine-dependent kinase inhibitor,transcription factor and so on.These proteins are involved in many physiological processes,such as cell cycle regulation,cell apoptosis,DNA repair and cell signal transduction.Therefore,abnormal UPP pathway can cause many diseases,such as the occurrence and development of multiple tumors,multidrug resistance and dissemination.Proteasome inhibitors?PIs?have become a research hotspot of anti-cancer drugs.Micro PET technology is a non-invasive imaging method,which can evaluate the metabolic level,biochemical reactions and functional activities of radionuclide-labeled drugs in various organs in vivo noninvasively,quantitatively and dynamically.It provides a new method for drug research.In this paper,20S proteasome inhibitors bortezomib and carfezomib were used as lead compounds to change the structure of peptide fragments.After synthesis,candidate drugs with good pharmacodynamics and pharmacokinetic properties were screened by in vivo and in vitro activity test.Methods:Inhibitor peptide fragments were screened based on 3D-QSAR of peptide inhibitors.Targets,F-19 compounds and F-18 markers were synthesized by liquid phase synthesis method.The pharmacodynamic and pharmacokinetic properties were evaluated by enzyme activity test in vitro and microPET technology for animal models.The structure-activity relationship was calculated by sybybl x 2.0 software.Results:32 intermediates and 12 target compounds were synthesized,including four radioactive probes.Their structures were characterized by ¹H-NMR,¹³C-NMR,MS and HPLC.The compounds M-2-b-¹⁹F and M-1-b-¹⁹F had good enzymatic activity in vitro.The compounds synthesized by Micro PET technology had good targeting,and the metabolic pathways of each compound were different.The physical and chemical properties of self are closely related.