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

Authors :: Huang Y
Sun G
Wang P
Shi R
Zhang Y
Wen X
Sun H
Chen C
Source :: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2018 Sep 15; Vol. 28 (17), pp. 2957-2960. Date of Electronic Publication: 2018 Jul 06.
Publication Year :: 2018
Abstract: In this study, Complex I inhibitor R419 was firstly revealed to have significant anticancer activity against HepG2 cells (IC <subscript>50</subscript>  = 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 (IC <subscript>50</subscript>  = 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.<br /> (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Subjects :: Antineoplastic Agents chemical synthesis
Antineoplastic Agents chemistry
Cell Death drug effects
Cell Proliferation drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Electron Transport Complex I metabolism
Enzyme Inhibitors chemical synthesis
Enzyme Inhibitors chemistry
Hep G2 Cells
Humans
Molecular Structure
Piperidines chemical synthesis
Piperidines chemistry
Structure-Activity Relationship
Antineoplastic Agents pharmacology
Electron Transport Complex I antagonists & inhibitors
Enzyme Inhibitors pharmacology
Piperidines pharmacology

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