Design And Synthesis Of Fluoroacylshikonin As Anticancer Agents

Lithospermum erythrorhizon is herb perennial in the family of Baraginaceae. There are three species, Xinjing Zicao(Arnebia euchroma (Royle) Johnst.)?Neimeng Zicao (Arnebia guttata Bunge)and Dian Zicao(Onosnla paniculatum Bur.et Franch.), in china. It is an important kind of medicinal plant which its root contain medicinal ingredient. Shikomn and its derivatives, a kind of naphthoquinones-like secondary metabolites synthesized in the roots or cultured cells of Boraginaceae plants, have good effect on anti-cancer, anti-inflammatory, anti-bacterium, antioxidant, wound healing and activating blood. The researches of natural medicine are still hot in researching tumor. Therefore the root of Lithospermum erythrorhizon is very important herb. Previous researches have demonstrated that Shikonin and its derivatives have good effect on anti-tumor, but it have a series of side effects, high toxicity for normal cells and low Solubility. Several researchers synthesized and evaluated numerous new shikonin derivatives, aiming at finding new anticancer drugs which are effective and have fewer side effects.For the conquering these side effects, a series of shikonin derivatives which acylated selectively by various fluorinated carboxylic acids at the side chain of shikonin, were synthesized and their anticancer activity evaluated, in which eight compounds were reported for the first time. Among all the compounds tested, compound S7showed the most potent anticancer activity against B16-F10(malignant melanoma cells), MG63(Human osteosarcoma cells) and A549(Lung cancer cells) with IC500.39?g/mL,0.72?g/mL and0.58?g/mL. Shikonin is an active naphthoquinone compound, which is mainly isolated from the roots of the traditional oriental medicinal herb Lithospermium erythrorhizon. Acharya and his group also demonstrated that naphthazarin is a microtubule inhibitor in cell-free systems and in A549cells. Naphthazarin induced cell death by activating apoptosis and autophagy pathways. Naphthazarin treatment could depolymerize interphase microtubules and disorganized spindle microtubules. These new research results have helped us in evaluating anticancer activity.Encouraged by these new finding mentioned above, we also designed an assay in which compounds (S1?S12) interact with tubulin. Compounds S7and S5showed strong inhibitory effect (S7, IC50=2.56?g/mL; S5, IC50=3.24?g/mL and Colchicine, IC50=1.50p,g/mL). Combining the above mentioned results, we inferred that S7and S5directly interacted with tubulin. Furthermore, docking simulation of compounds S7was carried out to position S7into tubulin active site to determine the probable binding conformation. All the results suggested that compound S7may be a potential anticancer agent.