Design,Synthesis And Antitumor Activity Evaluation Of Tricyclic Diterpene Analogs Comprising Cyanoenone Pharmacore

Tricyclic diterpenoids are reported to have various biological and pharmacological activities,such as anti-tumor,anti-inflammatory,anti-bacterial,and anti-virus activities.However,it's difficult to extract and purify the natural diterpenoids from plants.And the amounts of natural diterpenoids are not likely to meet the requirements of biological activity evaluation.Therefore,it is very important for new drug discovery based on various lead compounds which are obtained from screening the synthetic analogs of tricyclic diterpenoid.Colorectal cancer is the third most common cancer in morbidity and mortality worldwide.In this study,the diterpene analog compound B-1,containing cyanoenone in ring A,was synthesized following the synthetic methods of CDDO-Me.After structure modification and three rounds test on colon cancer cells(CSCs),compound B-20 was confirmed to have potent anti-tumor activity.Results showed that B-20 targets the BMI-1 gene and reduce the expression of BMI-1 protein,which has better activity and selectivity than the positive control PTC-209(BMI-1 inhibitor).In the further study,the expression of BMI-1 was reduced in a dose-dependent maner on compound B-20.Simultaneously,B-20 reduced CSCs proliferation and migration,demonstrating that B-20 is a promising compound against colon cancer.Breast cancer is a malignant tumor that occurs in the mammary gland epithelium,and the incidence was in the first place of female malignant tumors.Drug resistance is a serious phenomenon which hampers the success of cancer chemotherapy.It's necessary to develop new agents against drug-resistant breast cancer.By screening our synthetic library of diterpenoid-analogs on drug-resistant breast cancer cells MCF-7/ADR,we found that compound Z-8 has antitumor activity on MCF-7/ADR cells.Based on lead compound Z-8,we synthesized a series of tricyclic diterpenoid analogs and tested them on MCF-7/ADR.Results showed that the most potent compound Z-19 has better activity and selectivity than lead compound Z-8.Simultaneously,Z-19 can reduce the proliferation and migration on MCF-7/ADR cells,demonstrating that Z-19 is a potent and promising compound against breast cancer.