Synthesis and mechanisms of action of novel harmine derivatives as potential antitumor agents.
A series of novel harmine derivatives bearing a benzylindine substituent in position-1 of β-carboline ring were synthesized and evaluated as antitumor agents. The N2-benzylated β-carboline derivatives 3a-g represented the most interesting anticancer activities and compound 3c was found to be the most active agent to diverse cancer cell lines such as gastric carcinoma, melanoma and colorectal cancer. Notably, compound 3c showed low toxicity to normal cells. The treatment significantly induced cell apoptosis. Mechanistically, PI3K/AKT signaling pathway mediated compound 3c-induced apoptosis. Compound 3c inhibited phosphorylation of AKT and promoted the production of reactive oxygen species (ROS). The ROS scavenger, LNAC and GSH, could disturb the effect of compound 3c induced apoptosis and PI3K activity inhibitor LY294002 synergistically enhanced compound 3c efficacy. Moreover, the results from nude mice xenograft model showed that compound 3c treatment effectively inhibited tumor growth and decreased tumor weight. Collectively, our results demonstrated that compound 3c exerts apoptotic effect in cancer cells via suppression of phosphorylated AKT and evocation of ROS generation, which suggested that compound 3c might be served as a promising therapeutic agent for cancer treatment.
College of Life Sciences, Wuhan University, Wuhan, 430072, P. R. China.|School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan, 430070, P. R. China.
Xiao-Fei
XF
Zhang
School of Chemistry, Sun Yat-sen University, Guangzhou, 510275, P. R. China.
Rong-Qin
RQ
Sun
Renmin Hospital of Wuhan University, Hubei General Hospital, Wuhan, 430072, P. R. China.
Yi-Fan
YF
Jia
School of Chemistry, Sun Yat-sen University, Guangzhou, 510275, P. R. China.
Qing
Q
Chen
College of Life Sciences, Wuhan University, Wuhan, 430072, P. R. China.
Rong-Fu
RF
Tu
College of Life Sciences, Wuhan University, Wuhan, 430072, P. R. China.
Ke-Ke
KK
Li
College of Life Sciences, Wuhan University, Wuhan, 430072, P. R. China.
Xiao-Dong
XD
Zhang
College of Life Sciences, Wuhan University, Wuhan, 430072, P. R. China.
Run-Lei
RL
Du
School of Chemistry, Sun Yat-sen University, Guangzhou, 510275, P. R. China.
Ri-Hui
RH
Cao
D000072283:A549 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002867:Chromones; D006247:Harmine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009025:Morpholines; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D002867:Chromones; D006247:Harmine; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one