Synthesis and biological evaluation of Complex I inhibitor R419 and its derivatives as anticancer agents in HepG2 cells. Issue 17 (15th September 2018)

• Record Type: Journal Article
• Authors: Huang, Yaping; Sun, Geng; Wang, Pengfei; Shi, Rui; Zhang, Yanchun; Wen, Xiaoan; Sun, Hongbin; Chen, Caiping
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 17(2018)
• Page Start: 2957
• Page End: 2960
• Publication Date: 2018-09-15
• Subjects: Complex I -- R419 -- Flavonoids derivatives -- Human hepatocellular carcinoma; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.07.006
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical 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. Highlights: First report on anticancer activity of Complex I inhibitor R419 . Twenty R419 derivatives were synthesized. H20 is the most potent compound against HepG2 cells. H20 caused cellular ATP depletion and necrosis. H20 displayed inhibitory activity against Complex I. 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.