Study On The Synthesis And Preliminary Antitumor Activity Evaluation Of Combretastatin A4 Derivatives With Thiazolo[3,2-b] [1,2,4] Triazol-6(5H)-one Or Other Structural Fragments

Recently, cancer is a significant health concern in the modern world, and the leading cause of death after cardiovascular disease. But most anti-tumor drugs have obvious shortcomings, the typical of them are their contribution to multi-drug resistance and toxic side effect. Therefore, there has been a growing interest in the search for anti-tumor drugs with high efficacy, low toxicity and multi-drug resistance.The nature product combretastatin A4 has been research focus in cause of its a highly efficient anti-tumor activity. Especially, phosphate prodrugs Combretastatin A4P is currently in phase III clinical trials as tumor vascular targeting agent. But with the deepening of clinical trials, the researchers found that it can cause a collapse of blood vessels inside the tumor tissue quickly and selectively and block the blood supply, which cause ischemic necrosis of the tumor tissue as a new angiogenesis inhibitor. However, it is weak to remnants of the destruction of the tumor tissue, so it leads to the failure of chemotherapy easily. It is more and more important to design and synthesize a series of new derivatives of combretastatin A4 which have better efficacy.In our study, we retained the important trimethoxyphenyl pharmacophore and replaced some structure by thiazolo[3,2-6][1,2,4] triazol-6(5H)-one, 1,2,4-triazole-5-thione, schiff bas or cinnamic acid derivatives according to the principle of bioisosterism or other mechanisms.The structures of synthesized compounds were characterized by 1H-NMR, IR,13C-NMR and high resolution mass spectrometry, and the growth inhibitory activities in vitro were evaluated by MTT assay against HeLa, HCT116, BEL-7402 and L-02. The results showed that most of the synthesized compounds expressed inhibitory activities against the four cells lines. The anti-proliferation activities of compound 6d were increased greatly against HCT116, L-02, and BEL-7402 cell lines, but there was almost no inhibitory effect against HeLa cells, and 6d was more toxic to L-02 normal liver cells. Compound 5k,5m showed selective inhibitory effects against HeLa, HCT116, BEL-7402 cancer cells while no toxic to L-02 normal cells, so they have good subsequent research values in the future. The anti-tumor activities in vitro of 7a-7g were not strong, but all compounds were toxic to L-02 normal cells, the reason may be that the weight of every target molecule is too large and has poor water solubility, need to be further studied. All of the compounds 9a-9g expressed no significant anti-proliferation activities against the four kinds cell line, perhaps the reason is that when the polar groups as well as phenolic hydroxyl group of pterostilbene and carboxyl group of cinnamic acid derivatives, the lipid-water partition coefficient was increased excessively that compound couldn’t pass through the cell wall to express antitumor activity.