Structural Optimization And Evaluation Of Anti-Gastric Cancer Activity With Gramine-indole As Lead Compound

Gastric cancer(GC)is one of the most common malignancies worldwide with an increasing morbidity and mortality currently.There has been considerable progress in the treatment of gastric cancer with continuous development of surgery,chemotherapy,radiotherapy and biotherapy technology.However,GC is easy to metastasize and difficult to detect at the early stage because of its high infiltration,resulting in a lower therapeutic efficacy and higher mortality.Therefore,further studies on the discovery of novel drug candidates which could highly inhibit GC cells invasion and metastasis may provide a new therapeutic approach for gastric cancer treatment.Generally,gramine is an indole,which possesses diverse biological activities,but its anti-gastric activity is poor.On the other hand,the indole skeleton has been widely used in the construction of various drugs,especially for the treatment of tumors,which make it possible by optimizing the structure of the gramine to develop novel anti-gastric cancer candidates.Inspired by this,we constructed 29 novel gramine-indole containing compounds with the help of the pharmacophore fusion strategy.The different thiazole derivatives possessed five-membered heterocyclic rings introduced into the indole-based scaffold and used terminal alkyne group during structural modification to enhance the anti-gastric cancer activity.Structure-activity relationship(SAR)studies underlined the important role played by terminal alkyne that increased the inhibitory effect.After synthesizing the series of the novel compounds successfully,we used to evaluate the anticancer activity,among them,the compound 16h displayed the best anti-proliferative activity over gastric cancer MGC803 cells with IC50 value of 3.74μM.Further research proved compound 16h was able to introduce mitochondria-mediated apoptosis,caused cell cycle arrest G2/M phase.Additionally,compound 16h could successfully inhibit metastasis ability of MGC803 cells.Collectively,these studies may give new ideas for the structural optimization of the gramine to improve the anti-gastric cancer activity,and provide a potential candidate for the treatment of gastric cancer.By summarizing,the gramine contains indole moiety which actively used during drug discovery and development including anticancer agent,while some of the gramine-indole derivatives have been successful approved for clinical uses.Hence,gramine-indole moiety may be used as promising agent.