Synthesis and biological evaluation of Complex I inhibitor R419 and its derivatives as anticancer agents in HepG2 cells

  • Bioorg Med Chem Lett. 2018 Sep 15;28(17):2957-2960. doi: 10.1016/j.bmcl.2018.07.006.
Yaping Huang  1 ,  Geng Sun  1 ,  Pengfei Wang  1 ,  Rui Shi  1 ,  Yanchun Zhang  1 ,  Xiaoan Wen  1 ,  Hongbin Sun  2 ,  Caiping Chen  3
Affiliations
  • 1. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease and State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China.
  • 2. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease and State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China. Electronic address: [email protected].
  • 3. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease and State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China. Electronic address: [email protected].
PMID: 30001917 DOI: 10.1016/j.bmcl.2018.07.006
Abstract

In this study, Complex I inhibitor R419 was firstly revealed to have significant Anticancer activity against HepG2 cells (IC50 = 5.2 ± 0.9 μM). Based on this finding, a series of R419 derivatives were synthesized and biologically evaluated. As results, 9 derivatives were found to have obvious Anticancer activity. Among them, H20 exhibited the most potent activity (IC50 = 2.8 ± 0.4 μM). Mechanism study revealed that H20 caused severe depletion of cellular ATP, dose-dependently activated AMPK, decreased Bcl-2/Bax ratio and induced necrotic cell death. Most importantly, H20 displayed definite inhibitory activity against Complex I.

Keywords
Complex I; Flavonoids derivatives; Human hepatocellular carcinoma; R419.
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