Studies On Structural Modification And Radiosensitivity Of Tanshinone

Objective:Radiosensitizers can enhance suppression effect to tumor cells combined with radiation while have less effect on normal tissues. It is found that Tanshinone compounds (Tanshinone Ⅱ A, Tanshinone Ⅰ, Dihydrotanshinone, Cryptotanshinone) have cytotoxicity and radiosensitizing effects on tumor cells, we designed a series of derivatives with Tanshinone as leading compounds. Then, we studied their anti-tumor and radiosensitizing effects in vitro in order to find the rational positions for structural modification. This work will provide foundation (evidences) for further study.Methods:Derivatives were obtained by different reactions on A ring, D ring, at site of11and12of Tanshinone. The MTT assay was used to evaluate the cytotoxicity of leading compounds and their derivatives on HeLa cells, HepG-2cells and SGC-7901cells. The radiosensitizing effect was investigated by clonogenic assay through sensitizing enhancement radio (SER), with single-target multi-hit model.Results:(1) In this paper, a total of23derivatives were designed and synthesized,13compounds of them from leading compound Tanshinone II A, and6derivatives of them from leading compound Tanshinone I, and the rest objective compounds from leading compound Dihydrotanshinone. The structures of target compounds were confirmed by ESI-MS,1H-NMR and13C-NMR.17derivatives have been identified as new compounds.(2) Inhibitory effects of compound T1～T7, T9, T10, T13on tumor cells were stronger than their leading compounds. And the half inhibitory concentrations (IC50) to HeLa cells, HepG-2cells and SGC-7901cells of compound T7were6.24μM,10.24μM and4.22μM respectively, which were the most active derivatives of them. The antiproliferation effects of derivatives T14-T16, T19against HeLa cells were better than Tanshinone I, which was their leading compound. Then, the rest derivatives showed poor effects than their leading compounds respectively.(3) The clonogenic assay was performed to explore the radiosensitizing effect of derivatives T1-T4, T6-T10, T13, T20, T21and Dihydrotanshinone on HeLa cells. CompoundT3, T7, T13showed higher SER, when their cell survival curves were fitted with single-target multi-hit model. Furthermore, the highest radiosensitizing effect is up to1.44(SER), indicated that the derivative of T7had the better effect than Dihydrotanshinone (SER=1.39).Conclusion:CompoundT3, T7, T13showed higher SER, and the analysis of structure-activity relationship indicated that modification at A ring and D ring of Tanshinone could enhance its inhibitory activity and radiosensitivity on tumor cells in vitro. Moreover, if D ring was damaged or modified at site of11and12of Tanshinone, it may reduce or even lose activity, which mean the structure of o-quinone and D ring of Tanshinone are key groups to remain effect. Eventually, phase Ⅰ metabolites of Tanshinone showed higher inhibitory activity and radiosensitivity. It means that the process of phase Ⅰ metabolism may enhance activity of Tanshinone.