Design,Synthesis And Antitumor Activity Of Tanshinone Analogues

Cancer is the second leading cause of human death around the world.As one of the most common clinical treatment,chemotherapy is always recommended,especially in low-income and middle-income territories.Because of their"various chemical spaces",natural products have always held a place in the field of new drug development at present.As two typical O-quinone natural products,Tanshinone IIA andβ-lapachone showed excellent biological activities,such as antibacterial,insecticidal,antitumor,cardiovascular protection,and inhibition of neurodegenerative diseases.However,mostly worldwide researches just focused on the antitumor effects of Tanshinone IIA andβ-lapachone.It has been found that the presence of a saturated six-membered ring of tanshinone IIA has little effect on its antitumor activity.Whileβ-lapachone retain saturated oxygenated six-membered ring,it has obvious side effects on normal cells.Therefore,in the design process of this study,we tried to retain the furan ring of tanshinone IIA and removed saturated six-membered ring of tanshinone IIA.Based on these studies,we adopted a fusion design strategy that Tanshinone IIA andβ-lapachone fused into a mother nucleus of tanshinone analogue.We use 2-hydroxy-1,4naphthoquinone as the raw material,and react with 3-bromopropene to obtain 2 through Claisen rearrangement;then 2 was cyclized to get the ortho-quinone 3 by using Lewis acid;then Double radical reaction gives key intermediate 4.At last,at the C-2 position of the furan ring of mother nucleus,we initially obtained 27 target compounds of TB and TC series through a common coupling reaction（C-N,C-O）.Then,we obtain 23 derivatives of the TD series through a classic click reaction.The structures of these derivatives have been confirmed by analytical methods,such as ¹H NMR,¹³C NMR,infrared spectrum and HRMS.To three tumor cells,include prostate cancer PC3,leukemia K562,and melanoma WM9.We studied in vitro antitumor activity tests on TB and TC series derivatives.when amino acid fragments,heterocyclic fragments,and aromatic ring fragments containing electron-withdrawing groups or polysubstituents were introduced,We have found that the derivatives have excellent inhibitory activity,and when alkane fragments and aromatic rings containing electron donating groups were introduced,their inhibitory activities will increase.Nearly two thirds of the derivatives of the TB and TC series have excellent antitumor activity in vitro,and their inhibition rate exceeds 70%.Compound TB7(IC₅₀=2.981μM)showed inhibitory activity only against K562,which was comparable to the lead compound tanshinone IIA(IC₅₀=4.638μM),and was close to the in vitro antitumor activity of paclitaxel(IC₅₀=2.149μM);Compound TC7 showed inhibitory activity only against PC3,its IC₅₀ value is 1.507μM.and Compound TC7 showed inhibitory activity only against PC3,which was brilliant than the inhibitory activity of positive control group in vitro.Therefore,compound TB7 and compound TC7showed some selective antitumor activity in virto.In addition,To four tumor cells,include leukemia K562,prostate cancer PC3,prostate cancer LNCa P,and human breast cancer MDA-231.We studied in vitro antitumor activity tests on TD series.Preliminary screening results showed that the TD series has reproductive cells toxicity in vitro,and it deserve further study.The active compound TC7 inhibits cell proliferation by inducing apoptosis.And it exhibits excellent selectivity in vitro antitumor activity.It has the possibility to be a"star drug molecule",and it is worthy of futher development and research...