2. Academic Validation
  3. 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

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

  • Eur J Med Chem. 2016 Nov 29:124:809-819. doi: 10.1016/j.ejmech.2016.09.005.
Zhuang Song 1,  Cai-Ping Chen 1,  Jun Liu 2,  Xiaoan Wen 1,  Hongbin Sun 3,  Haoliang Yuan 4
Affiliations

Affiliations

  • 1 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.
  • 2 China Jiangsu Center for Drug Screening, China Pharmaceutical University, 24 Tong Jia Xiang, Nan Jing 210009, PR China.
  • 3 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.
  • 4 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.
PMID: 27643639 DOI: 10.1016/j.ejmech.2016.09.005
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.

Keywords

3-Ylideneoxindole; Antitumor agent; Apoptosis; Reactive oxygen species (ROS); Thioredoxin reductase (TrxR).

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