Synthesis Of Tanshinone Ⅱa-imidazole Derivatives And Its Antitumor Mechanism

At present,although the types of tumor treatment and chemotherapy drugs are increasing,chemotherapy drugs are still faced with great toxicity and poor targeting.In recent years,due to the low toxicity of natural products,multi-target and other advantages of more and more attention,but most of the natural products have low solubility,poor bioavailability and other shortcomings.Therefore,structural modificationnatural products,improvement of solubility and bioavailability,and search for a class of natural product derivatives with low toxicity and good targeting are expected to become potential anti-tumor drugs.Many literatures reported that Tanshinone IIA derivatives have good anti-inflammatory,antibacterial and antitumor effects,but they are also faced with the problems of low solubility and low bioavailability.This paper focuses on the design and synthesis of a series of IIA imidazoles derivatives of Tanshinone to further study their anti-tumor effects and anti-tumor mechanisms and their targets.The main research of this paper is as follows:(1)Tanshinone IIA imidazole derivatives 1 and 2 were designed and synthesized.Electron absorption spectrophotometry,fluorescence emission spectra and molecular docking were used to find that both compounds could specifically bind and stabilize c-myc G4-DNA in the way of planar insertion,and the binding effect of compound 1 was stronger.Through MTT,we found that the anti-tumor activity of compound 1 was better than that of compound 2.In order to further explore the mechanism,flow cytometry was used,and the results showed that compound 1 played an anti-tumor role by promoting apoptosis.Subsequently,we also found that compounds 1 and 2 can induce and remove more reactive oxygen species and superoxide anions.(2)Design and synthesis of Tanshinone IIA imidazole derivatives 3.Through MTT,we found that compound 3 showed activity on a variety of tumor cells,especially on MDA-MB-231 cells of triple-negative breast cancer,but showed low toxicity on MCF-10A cells of normal breast epithelial cells.Subsequently,we explored the inhibitory effect of compound 3 in the model of breast cancer tumor zebrafish(flila:EGFP)in vivo,and found that compound 3 could inhibit the proliferation,invasion and metastasis of MDA-MB-231 cells both in vivo and in vitro.Through the luminal formation experiment and the zebrafish angiogenesis experiment,we further found that compound 3 can also inhibit the formation of new blood vessels in vitro and in vivo,and cut off the nutrient source and metastasis pathway of tumor cells.The anti-tumor mechanism of compound 3 was further studied by flow cytometry,immunofluorescence,Western Bolt and qPCR.We found that compound 3 can significantly down-regulate g-rich gene sequence,regulate g4-dna damage to DNA,and affect DNA damage repair mechanism,thus inducing MDA-MB-231 cell cycle arrest and apoptosis.To sum up,this paper successfully design synthesis three tanshinone type IIA imidazoles derivatives as a potential tumor inhibitor,three compounds could be regulated and controlled by G4-DNA,influence on DNA damage and DNA damage repair mechanisms induced by MDA-MB-231 cell cycle arrest and apoptosis,thus inhibiting invasive pseudopodia formation and inhibit the formation of new blood vessels synergy to inhibit breast cancer MDA-MB-231 cells proliferation,invasion and metastasis.