Design And Synthesis Of Tricyclic Diterpene Analogs And Evaluation Of Their Antitumor Activity In Castration Resistant Prostate Cancer

Prostate cancer(PCa)is one of the most common male cancers,it is a serious threat to the aging males' health.The majority of patients have been found in the advanced-stage prostate cancer and required to undergo androgen deprivation therapy,and almost all patients will gradually progress to castration-resistant prostate cancer(CRPC)in 1-2 years later.Studies have shown that prostate cancer is closely related to androgen receptor(AR)in CRPC.Targeting the AR signaling pathway is one of the most effective treatments for PCa.In recent years,most of the clinical anti-PCa drugs are targeted to ligand binding domain(LBD)of AR.And with AR mutations produced mutant AR-Vs(lack of LBD or no complete LBD),the CRPC patients become resistant to the LBD domain related first-line drugs Abiraterone and MDV3100 for producing mutant AR-Vs(lack of LBD or with an incomplete LBD).For the resistance to existing drugs,so it has a good prospect for development of new anti-castration resistant prostate cancer drugs to overcome drug resistance.We have established a library of tricyclic diterpenoid analogs.The library was screened with three different types of prostate cancer cell lines,including DU 145 cells(AR-)which do not express AR,LNCaP(AR-FL)which express the full length AR and 22RV1(AR-FL and AR-Vs)which express both the full length AR and the splice variant AR-Vs at the same time for anti-proliferation activity.Results showed that compound 5 displayed poor antitumor activity on DU 145 and potent antitumor activity on LNCaP and 22RV1.A series of tricyclic diterpene analogs containing different types of heterocyclic amines were synthesized based on the lead compound 5 and their anti-prostate cancer activity were tested.Tricyclic diterpene analogs containing benzo-heterocyclic amines are beneficial to the increase in activity,Benzene heterocyclic amine derivatives are beneficial to the increase of activity and have good inhibitory activity against LNCaP and 22RV1.The potent compounds 5,8,9,10,12 and 20 were selected for further study with luciferase experiments.The results showed that these selected compounds inhibited the transcriptional activity of AR-FL and AR-Vs(AR-V7 and AR-V567es)obviously.The inhibition rate of the most potent compound 10(10 ?M)for AR-FL,AR-V7 and AR-V567es was 42%,64.5%and 77.2%respectively.The inhibition of the transcriptional activity of compound 10 for AR-V7(IC50 = 7.50 ?M)and AR-V567es(IC50 = 8.81 ?M)was better than that of the positive control compound EPI-001.Compound 10(5 ?M)almostly inhibited the clonal formation of LNCaP(AR-FL)and VCaP(AR-FL and AR-Vs)cells,and inhibition was better than that of positive control EPI-001 and negative control MDV3100.Subsequently,we will test the anti-prostate cancer effects in rats.The synthesis of molecular probes and using synthetic probes for mechanism exploration are in progress.The work of this thesis has great significance to overcome the resistance of existing drugs in treatment of CRPC disease.