Design, Synthesis and Biological Evaluation of Ligustrazine-Flavonoid Derivatives as Potential Anti-Tumor Agents.

In the clinic some anti-tumor drugs have shown damage to normal blood vessels, which could lead to vascular diseases. Therefore, it is necessary to evaluate the effects of anti-tumor drugs on normal blood vessels at the beginning of the drug design process. In this study, ligustrazine (TMP) and flavonoids were selected as raw materials. Sixteen novel TMP-flavonoid derivatives were designed and synthesized. Interestingly, compounds 14 and 16 were obtained by hydrolysis of a dihydroflavone to a chalcone under alkaline conditions. The cytotoxicity of the TMP-flavonoid derivatives was evaluated on five human tumor cell lines and one classical type of normal endothelial cell lines (HUVEC-12) by an MTT assay. Part of the derivatives showed better anti-tumor activities than the corresponding raw materials. Among them, compound 14 exhibited the closest activity to the positive control against the Bel-7402 cell line (IC50 = 10.74 ± 1.12 μM; DDP IC50 = 6.73 ± 0.37 μM) and had no toxicity on HUVEC-12 (IC50 > 40 μM). Subsequently, fluorescence staining and flow cytometry analysis indicated that compound 14 could induce apoptosis of Bel-7402 cell lines. Moreover, the structure-activity relationships of these derivatives were briefly discussed.