Structural Modification Of Actein From Cimicifuga Foetida And Toosendanin From Melia Toosendan And The Anti-TNBC Activities

This paper consists of three chapters.The first chapter elaborates the structural modification of actein and its anti-triple-negative breast cancer activity;the second chapter describes the structural modification of toosendanin and its anti-triple-negative breast cancer activity;the third chapter introduces the research progress of anti-triple-negative breast cancer.Chapter 1:Structural modification and anti-triple negative breast cancer activity of actein derivativesThis chapter focuses on a natural triterpenoid glycoside actein isolated from the rhizomes of the Traditional Chinese Medicine Cimicifuga foetida,which has previously been shown to have potential in the treatment of breast cancer.Based on the previous investigation,we designed and synthesized a series of actein derivatives and evaluated the anti-triple negative breast cancer（TNBC）activity of the synthetic derivatives in vitro.Of which,the most promising derivative 1-27 exhibited significant inhibitory activity against human TNBC cell lines HCC1806 and MDA-MB-231,with IC₅₀ values of 2.78 and 9.11μM,respectively.Structure-activity relationships of actein derivatives were also discussed.Moreover,preliminary mechanism investigation revealed that 1-27 significantly inhibited cancer cell proliferation via cell cycle arrest at S phase.In addition,Western blot showed that compound 1-27 induced p21 accumulation in a dose-dependent manner and apoptosis was induced by p38 pathway of MAPK signal.Overall,these results indicate that 1-27 has the potential to be developed as a lead compound and compounds with the actein scaffold are a promising new class of inhibitors to treat TNBC.Chapter 2:Structural modification of toosendanin and its anti-triple negative breast cancer activityThis chapter focuses on toosendanin（TSN）,a natural anticancer compound isolated from Melia toosendan Sieb et Zucc,a Traditional Chinese Medicine.However,previous studies have shown that the efficacy of TSN in the treatment of triple negative breast cancer（TNBC）remains unsatisfactory.In this work,we investigated TSN and its derivatives in terms of their actions against MDA-MB-231 and HCC1806 TNBC cell lines.The results indicated that TSN and its derivative 2-11 showed excellent antitumor activity.Preliminary mechanistic studies showed that both compounds TSN and 2-11 induced S-phase arrest and G2/M phase cell number increase in HCC1806 cells.Strikingly,TSN and2-11 significantly reduced the protein level of the well-known tumor gene p53,reduced the phosphorylation of AKT and ERK,and induced the accumulation of phosphorylated p38and p21.Chapter Three:Research progress of TCM monomer against triple negative breast cancerThis chapter reviews the research on the anti-triple negative breast cancer of traditional Chinese medicine monomer,mainly focusing on the anti TNBC activity of monomer compounds and their derivatives extracted from plants,animals and minerals.In addition,the treatment of TNBC with compounds from Traditional Chinese Medicine combined with anticancer drugs such as paclitaxel,cisplatin and adriamycin are also described.It is hoped that the active compounds from Traditional Chinese Medicine can be modified to obtain new inhibitors with better anti TNBC activity,so as to help treat triple negative breast cancer patients,reduce the overexploitation of Traditional Chinese Medicine resources,and achieve the recycling of resources.