Structural Modification And Antitumor Activity Of Rubescensine A And Tanshinone ⅡA

Recently,malianant tumours have become a serious health issue as their incidence has been increasing yearly.So far,drug therapy is still an effective and important method in the clinical treatment of cancer.One of the major obstacles to the druggability of compounds with effective antitumour activity is their toxicity to normal cells.Therefore,the development of novel anticancer agents with lower toxicity to normal cells is needed.Natural products play a leading role in drug discovery and structural modifications of active natural products is an effective way of discovering potentially active molecules,lead compounds,and new drugs.This paper is divided into three parts:(1)synthesis and evaluation anticancer activity of the C-17 analogs of Oridonin;(2)synthesis and evaluation in vitro and in vivo anticancer activity of the C-14 analogs of Oridonin;(3)synthesis and biological activity of Tanshinone ⅡA derivatives as HIF-1α inhibitors.In the first part,a series of oridonin derivatives with substituted benzene moieties at the C17 position were designed,synthesized,and evaluated for their antiproliferative properties.Most of the derivatives displayed antiproliferative effects against AGS,MGC803,Be17402,HCT116,A549,and HeLa cells.Compound S16(IC50=1.05 μM)exhibit the most potent antiproliferative activity against HCT116 cells;it was more potent than oridonin(IC50=6.84 μM)and 5-fluorouracil(5-FU)(IC50=24.80 μM).The IC50 value of S16 in L02 cells was 6.5-fold higher than that in HCT116 cells.Overall,it exhibit better selective antiproliferative activity and specificity than oridonin and 5-FU.Compound S16 arrested HCT116 cells at the G2 phase of the cell cycle and increased the percentage of apoptotic cells to a greater extent than oridonin.In the second part,a series of novel oridonin derivatives bearing various substituents on the 14-OH position were designed and synthesised.Their antitumour activity was evaluated in vitro against three human cancer cell lines(HCT116,BEL7402,and MCF7).Most tested derivatives showed improved anti-proliferative activity compared to the lead compound oridonin and the positive control drug 5-fluorouracil(5-Fu).Among them,compound S48(IC50=0.16μM)exhibited the most potent anti-proliferative activity against HCT116 cells;it was about 43-and 155-fold more efficacious than that of oridonin(IC50=6.84 μM)and 5-Fu(IC50=24.80 μM)in HCT116 cancer cells.Interestingly,the IC50 value of compound S48 in L02 normal cells was 23.6-fold higher than that in HCT116 cells;it exhibited better selective anti-proliferative activity and specificity than oridonin and 5-Fu.Furthermore,compound S48 possibly induced cell cycle arrest and apoptosis by regulating the p53-MDM2 signalling pathway.Notably,S48 displayed more significant suppression of tumour growth than oridonin in colon tumour xenograft models where the tumour growth inhibition rate was 85.82%.Therefore,compound S48 could be a potential lead compound for the development of a novel antitumour agent.In the third part,a series of novel Tanshinone Ⅱ A derivatives bearing various substituents on the C-1 or C-15 position were designed and synthesised.All 21 novel compounds were confirmed by 1H-NMR and HR-MS.The inhibitory effects of all the derivatives on HIF-la transcriptional activity were tested by HRE Luciferase reporter assay after treatment of Heap3B cells under hypoxic conditions.The IC50 of the ihibitory activity of the C-1 position of Tanshinone Ⅱ A and the tetrahydropyrrole derivative S79 combined with succinic anhydride to HIF-1α was(),and the cytotoxic IC50 was 84.77 μM.There is value for further modification or developmentIn summary,this paper designed and synthesized 80 novel derivatives by structural modification of the natural products Rubescensine A and Tanshinone A.Three candidate compounds(S16,S48 and S82)with potential for development in cancer treatment were also found.It has certain reference significance for the development and utilization of anti-cancer natural products.