title: Design, synthesis, and biological evaluation of (2E)-(2-oxo-1, 2-dihydro-3H-indol-3-ylidene)acetate derivatives as anti-proliferative agents through ROS-induced cell apoptosis.
abstract: A novel class of (2E)-(2-oxo-1, 2-dihydro-3H-indol-3-ylidene)acetate derivatives were designed and synthesized as potent anti-proliferative agents. Most of these compounds showed potent anti-proliferative activity against some tumor cell lines, including SK-BR-3, MDA-MB-231, HCT-116, SW480, Ovcar-3, HL-60, Saos-2 and HepG2. Compounds 8c and 11h were identified as the most potent ones, while HL-60, HCT116 and MDA-MB-231 were the most sensitive cell lines. Mechanistic study revealed that compound 8c enhanced reactive oxygen species level by inhibiting TrxR and then induced apoptosis by activating apoptosis proteins, bax and cleaved-caspase 3 in HCT116 cells. Preliminary SAR analysis indicated that modifications of the double bond and ester group made great effects on the anti-proliferative activity. Our findings suggested that it was worth further studies on the antitumor potency of (2E)-(2-oxo-1, 2-dihydro-3H-indol-3-ylidene)acetates.
authors.affiliation: Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tong Jia Xiang, Nan Jing 210009, PR China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nan Jing 210009, PR China.
authors.forename: Zhuang
authors.initials: Z
authors.lastname: Song
authors.affiliation: Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tong Jia Xiang, Nan Jing 210009, PR China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nan Jing 210009, PR China.
authors.forename: Cai-Ping
authors.initials: CP
authors.lastname: Chen
authors.affiliation: China Jiangsu Center for Drug Screening, China Pharmaceutical University, 24 Tong Jia Xiang, Nan Jing 210009, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tong Jia Xiang, Nan Jing 210009, PR China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nan Jing 210009, PR China.
authors.forename: Xiaoan
authors.initials: X
authors.lastname: Wen
authors.affiliation: Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tong Jia Xiang, Nan Jing 210009, PR China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nan Jing 210009, PR China. Electronic address: hbsun2000@yahoo.com.
authors.forename: Hongbin
authors.initials: H
authors.lastname: Sun
authors.affiliation: Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tong Jia Xiang, Nan Jing 210009, PR China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nan Jing 210009, PR China. Electronic address: yhl@cpu.edu.cn.
authors.forename: Haoliang
authors.initials: H
authors.lastname: Yuan
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D017382:Reactive Oxygen Species; D013880:Thioredoxin-Disulfide Reductase
keywords: 3-Ylideneoxindole; Antitumor agent; Apoptosis; Reactive oxygen species (ROS); Thioredoxin reductase (TrxR)