Development Of New Anti-tumor Drugs From Natural Five-ring Triterpenoid Products

Cancer stem cells(CSCs)are considered to be the underlying cause of cancer occurrence,development,drug resistance and relapse.The development of small molecules that scavenge CSCs is a hot trend in medicinal chemistry research.However,molecules that selectively remove CSCs are rare,and the lack of lead compounds is an important reason for restricting the development of new drugs targeting CSCs.Structural modification and optimization of natural products and research on its structure-activity relationship to obtain lead compounds is one of the important ways to develop new drugs.According to reports in the literature,natural pentacyclic triterpenoids have a wide range of anti-tumor activity,and also have anti-inflammatory and liver-protecting effects.Previous research by our group showed that certain natural products containing unsaturated double bonds have the effect of scavenging CSCs.In this paper,the structure of oleanolic acid,ursolic acid and glycyrrhetinic acid was used as the mother nucleus.Sixty novel compounds with independent intellectual property rights were obtained through semi-synthetic modification,including 22 ursolic acid derivatives,19 oleanolic acid derivatives and 19 glycyrrhetic acid derivatives.These derivatives were screened for tumor cell proliferation activity and tumor microsphere formation activity in vitro.Finally,two lead compounds,OA-5 and OA-18,were obtained to inhibit tumor activity in vitro and remove cancer stem cells.Subsequently,it was evaluated on a mouse tumor-bearing model,and it was found that OA-5 and OA-18 have an effect of inhibiting proliferation of various tumors in vivo.Through the work of this subject,we found two compounds with anti-CSCs activity,which provide a new design idea for further development of new anti-CSCs drugs.