Design,Synthesis And Anti-Cancer Cells Activity Evaluation Of Combretastatin Derivatives

Part Ⅰ Design,synthesis and anti-hepatocarcinoma activity evaluation of combretastatin derivatives containing arylamide.Combretastatin A-4（CA-4）is a natural stilbene compound,exhibiting potent cytotoxicity to a variety of cancer cells.The combretastatin A-4 Phophate（CA-4P）,a phosphate derivative of CA-4,is developing as a broad-spectrum anti-cancer agent.CA-4 can bind to the colchicine binding site on the tubulin of cancer cells,which results in inhibiting the polymerization of microtubuleα-subunit andβ-subunit,preventing cancer cells from normal mitosis and causing cells apoptosis,so as to eliminate or inhibit the proliferation of cancer cells.However,due to the potent lipotropy of CA-4,the olefin double bond can easily change from the more active cis-conformation to the lower active trans-conformation,which severely limits its efficacy and clinical application in vivo.In addition,it has been reported that many small molecule drugs has been put on the market containing arylamide group,such as imatinib,which is an anti-tumor drug.The arylamide group of imatinib is an essential pharmacophore group for antitumor activity.Moreover,the electron-rich amide structure can accept or donate electrons,and easily establish various connections with amino acid residues on the target,such as hydrogen bonds,hydrophobic interactions,van der Waals forces and dipole-dipole interactions,which is becoming more and more important in the field of pharmaceutical chemistry.In summary,taking combretastatin A-4 as the lead compound,referring to structure-activity relationship of combretastatin A-4 and its analogues and combining the our previous research results,for the first time we introduced an arylamide into the para-position of B ring of CA-4 derivatives and obtained a total of 11 novel structural arylamide-containing combretastatin derivatives.The in vitro anti-proliferative activity of these compoundswas was evaluated on two human liver cancer cell lines BEL-7402、Hep G-2 and a human normal liver cell L-02.The results have shown that most of the synthesized compounds have good inhibitory activity on human liver cancer cells.To our delight,（Z）-N-(4-（2-cyano-2-（3,4,5-trimethoxybenzene vinyl）phenyl）-3,4,5-trimethoxybenzamide（8g）shows the best anti-hepatocarcinoma activity and display low toxicity on normal human liver cell.The possible binding mode of 8g with target protein was also studied by protein molecular docking.And the result extremely explain the high selectivity of 8g.In view of the excellent performance of 8g,we think it is a promising lead compound.Part Ⅱ Design,synthesis,antitumor activity,and water solubility evaluation of combretastatin derivatives with water soluble groups.In order to improve the water solubility of combretastatin derivatives,we co-opted the previous research in our laboratory and combined with classical methods to improve the water solubility of combretastatin derivatives to yield 18 different nitrogen-containing substitutions.The MTT assay was applied to evaluate the biological activity of these compounds in four human cancer cells and two normal human cells.And their water solubility was measured by ultraviolet spectrophotometry.The results showed that the synthesized compounds had a lower inhibitory activity on cancer cells when compared with the positive control CA-4,but they were less toxic to normal human cells than CA-4.In terms of solubility,compared to CA-4,the three compounds containing 4-methylpiperazine ring have better water solubility.Considering the activity and water solubility of the compound,（Z）-N-（4-（2-cyano-2-（3,4,5-trimethoxyphenyl）vinyl）-3-methylphenyl）-2-（4-methylpiperazine-1-yl）acetamide hydrochloride（22a₆）is an ideal compound,which reserves further research.