Design,Synthesis And Bioactivity Evaluation Of Chalcone Tryptophan Derivatives With Antitumor And Anti-Inflammatory Activities

The number of cancer deaths is the second in the world.Cisplatin is a drug commonly used in the clinical treatment of cancer,but some patients who receive cisplatin will suffer acute kidney injury caused by kidney inflammation.At present,a variety of natural products with anti-inflammatory activity have been used in the study of acute kidney injury induced by cisplatin.Our research group has previously synthesized a series of compounds with kidney protective effect,but the anti-tumor activity is not high enough to effectively reduce the dosage of cisplatin.Clinically,there is a lack of drugs that can effectively inhibit the growth of tumor cells and have a protective effect on the kidney.Chalcone is a kind of natural product with a wide range of anti-tumor and anti-inflammatory activities,but its application is limited by the disadvantages such as high cytotoxicity and poor water solubility.L-tryptophan is one of the important natural amino acids in physiological metabolism,with high water solubility,high bioavailability and other excellent properties,and has been widely used in the design of anti-tumor and anti-inflammatory compounds.Therefore,chalcone and tryptophan fragments were combinated to obtain the maternal structure in this project.According to the principles of steric hindrance,electron-induced effect and hydrogen bond number,34 new compounds with chalcone-tryptophan framework were designed and synthesized.Firstly,the anti-tumor activity of the compounds was screened,and most of the compounds showed good anti-tumor activity at the cell level.16 compounds with good antitumor activity were used to screen for kidney protective activity.Among them,6v not only had good antitumor activity(IC₅₀=2.02±0.75μM),but also had a certain kidney protection effect.At 4μM,the survival rate of HK-2 cells stimulated by cisplatin increased from 39.1%to 52.2%.In the study of anti-tumor mechanism,6v can significantly change the cell morphology and migration ability,arrest the cell cycle in the G2/M phase,and induce cell apoptosis by decreasing Bcl-2 protein and increasing Bax protein.EBI competitive experiments demonstrated that 6v could bind to colchicine sites of tubulin,thereby inhibiting tumor cell proliferation.Molecular docking experiment assisted to prove that 6v had good binding with amino acid residues around colchicine site.In the study of kidney protective mechanism,Real-time PCR and ELISA experiments verified that the anti-inflammatory effect of 6v at the gene and protein levels was positively correlated with kidney protective activity,which proved that 6v played a kidney protective role through anti-inflammatory pathway.At the same time,the anti-tumor effect of 6v combined with cisplatin was evaluated,6v could cooperate with cisplatin to inhibit the proliferation of tumor cells and reduce the survival rate of HGC-27 to 17%at 4μM.At the same time,under the same inhibitory effect,6v combined with cisplatin can significantly reduce the dosage of cisplatin and reduce the damage of cisplatin to normal cells and kidneys.