Study On The Chemical Synthesis Of Vanillin Derivatives And Its Anti-Colorectal Cancer

With the increase of population aging,mortality rate of cancer will be the highest of all diseases in the future.Colorectal cancer(CRC)is clinically common and reftactroty tumor,its morbidity is increasing year by year.Survey data showed that the incidence of CRC ranks third and its mortality ranks second in the world.As a traditional cancer treatment method,chemotherapy has played an important role in the progress of cancer struggles.There are so many advantages which can be found in the chemotherapy such as reduce the preoperative tumor volume,improve the patient's postoperative quality of life,reduce the chance of recurrence and prolong the survival time.However,effects of chemotherapy will wear off over time.In addition,intratumoral heterogeneity and the side effects of chemotherapy will lead to failure of treatment,which limited the clinical application of chemotherapy.All in all,to avoid the drug resistance and decreased the side effects of chemical drugs,it is necessary to find a new "high-efficiency and low-toxic" chemotherapy molecule for the treatment of colorectal cancer at this stage.Natural products are a valuable resource for the cancer chemotherapeutic drugs.Nowsdays,the great number of anti-cancer molecules have been isolated from natural products such as paclitaxel,camptothecin and vincristine.So it is a good strategy to find a candidate molecule from natural products.Vanillin,a natural product,isolated from the pods of the plant vanilla.Study found that vanillin can be used to anticancer and antibacterial.However,the anticancer activity of vanillin is very poor.In order to improve the anticancer activity of vanillin,a series of structural modifications are needed.Fortunately,imidazole [4,5-f] [1,10] phenanthroline,as an excellent metal chelating agent,have a good inhibitory effect on lung adenocarcinoma cells A549.Therefore,the reaction of vanillin and imidazole [4,5-f] [1,10] phenanthroline may be a good direction to improve the anticancer activity of vanillin.In this study,Vanillin Derivatives Database(Vanillin Derivatives Database,VDD)had been constructed.After that,HT29 and HCT116 cell lines were used to screen the antitumor activity of vanillin derivatives.Results of MTT showed that 2-hydroxy-3 methoxybenzaldehyde have a better anticancer effects than vanillin.Hence,we had obtained two vanillin derivatives which called IPM711 and IPM712.The antitumor activities of IPM711 and IPM712 were studied at the cellular level.Results showed that cell proliferation of HCT116 and HT29 could be inhibited by IPM711 in a lower concentration range.In addition,invasion and migration of tumor cells can be inhibited by IPM711 too.Mechanism research indicates that the anticancer effect of IPM711 may be caused by regulating Wnt/?-catenin signaling pathway in HT29 cell lines.Studied on the IPM712 showed that it could inhibit the proliferation of colorectal cancer cells in the range of 1.4-2.5 ?M.Moreover,IPM712 could inhibit the formation of HCT116 cell clones and migration of HCT116 and SW480 cells.What's more,we found that the apoptosis of the two cell lines could be induced by IPM712.Mechanism research indicated that IPM712 played a role in regulate PI3K/AKT signaling pathway.Results of acute toxicity test suggested that single administration of high concentration may cause slight liver and heart toxicity in mice.Although we found that the anti-tumor activity of IPM712 has been greatly improved compared with IPM711,its toxicity to normal cells has been enhanced too.Therefore,it is very necessary to find a new modification to reduce the toxicity of IPM712 in the next work.In brieif,a vanillin structure database composed of 169 vanillin derivatives had been established in this work.IPM711 and IPM712 were synthesized by the vanillin and imidazole [4,5-f] [1,10] phenanthroline after a series of the anticancer activity evaluating on the selected compounds.The results of all the experiment show that the anti-cancer effects of vanillin derivatives IPM711 and IPM712 have been greatly improved compared with vanillin.