Design And Synthesis Of Aryl Piperazine Derivatives And Anti Prostate Cancer Activity Research

Cancer Prostate (PCa), a common malignant tumor of the urinary and reproductive system in middle aged and elderly men, is a solid tumor with a mortality rate of second. The pathogenesis of prostate cancer is inconclusive, but it can be determined that prostate cancer is closely related to androgen and its receptor (Androgen Receptor, AR). The study found that AR has a certain degree of expression in all stages of prostate cancer, thus being the main target of prostate cancer treatment.Endocrine therapy is the main method for the treatment of advanced prostate cancer. The effect of castration therapy in the early stage of prostate cancer treatment is good, but most of the patients will be resistant to the castration in the process of treatment and become castration resistant prostate cancer finally (Castration-Resistant Prostate Cancer, CRPC). The study found that once the tumor cells become resistant to androgen, the drugs used to treat almost can't improve the treatment outcome or survival rate, although they can relieve the pain of patients to a certain extent. Therefore, it is urgent to invent and develop more effective and safer anti prostate cancer drugs.In view of the adverse reactions and side effects of AR targeted therapy drugs in clinical application, a total of 52 new arylpiperazine derivatives were designed and synthesized by using 4-(bromomethyl) phenylacetic acid as raw materials on the basis of the study arounding naftopidil and its core-arylpiperazines, namely aryl piperazine derivatives 2-5-2-29 and 2-5'-3-31'. Cytotoxic activities of ether arylpiperazine derivatives 2-5-2-29 and 2-5'-2-31'were evaluated against PC-3, LNCaP, DU145 and RWPE-1 by CCK-8 assay. And we also discuss their structure activity relationship on the basis of the data result in order to find more efficient and safe anti prostate cancer drugs.This first chapter describes the the research status of prostate cancer at home and abroad including etiology, pathogenesis, diagnosis and therapeutic methods of prostate cancer, the research progress of AR targeted anti androgen drugs and the content and significance of our study.The second chapter reports that a total of 52 new ether aryl piperazine derivatives were designed and synthesized, by using 4-(bromomethyl) phenylacetic acid as raw materials, namely arylpiperazine derivatives 2-5?2-29 and 2-5'?3-31'. And we also cultivate the crystal morphology of some of the derivatives.The specific synthetic route of target compounds were designed through the inverse synthesis analysis and the antitumor activity of the target compounds were determined by CCK-8 method.The third chapter reports that all the derivatives were identified by 1H NMR, 13C NMR, HRMS/ESI-MS, and elemental analysis. And the cytotoxic activity in vitro was determined by CCK-8 method of ether aryl piperazine derivatives 2-5-2-29 and 2-5'-2-31'on PC-3, DU145, LNCaP and RWPE-1, compared with naftopidil. The results show that the compound 2-14,2-17, 2-18,2-20,2-21,2-23,2-24,2-26 and 2-27 have a strong activity on the test cells (IC50< 3 ?M). Moreover, these compounds show weak activity in normal human prostate epithelial cells. In addition, compound 2-14 and compound 2-23 showed the best cytotoxic activity against PC-3. Studies on the structure activity relationship of 2-5-2-29 showed that the introduction of the -OCH3 and Cl atoms could obviously enhance the activity of PC-3. Compounds 2-5',2-10',2-28',2-29'and 2-30'showed very strong activity on test cancer cells (IC50< 3 ?M) and weak activity on normal human prostate epithelial cells. Compounds 2-10'and 2-29'showed the best cytotoxic activity against PC-3 cells. The structure activity relationship of 2-5'-2-31'showed that para substitutions were beneficial to improve the anticancer activity of compounds.The fourth chapter summarizes the full text, and introduces the previous work on the screening of several compounds with better activity for further in-depth study.By discussing their structure activity relationship, we hope to provide a reference for more effective and safer anti prostate cancer drug research.