ABSTRACT
The article "Three new ent-abietane diterpenoids from the roots of Euphorbia fischeriana and their cytotoxicity in human tumor cell lines", written by Minghui Li, Fang He, Yuan Zhou, Meigui Wang, Pingde Tao, Qingmei Tu, Guanghui Lv, Xintao Chen, was originally published electronically on the publisher's internet portal (currently SpringerLink) on 17 April 2019 with open access. With the author(s)' decision to step back from Open Choice, the copyright of the article changed on 4 September 2020 to © The Pharmaceutical Society of Korea 2020 and the article is forthwith distributed under the terms of copyright. The original article has been corrected.
ABSTRACT
Human lactate dehydrogenase A (LDHA) plays a critical role in the glycolytic process, making the enzyme an ideal of anti-cancer drug target. Herein, we report the discovery of novel potent LDHA inhibitors by screening an in-house library. The hit-to-lead modification enabled us to identify compound 24c, which inhibited LDHA activity with an EC50 value of 90â¯nM, and reduced MiaPaCa-2 cancer cell proliferation with an IC50 value of 2.1⯵M. In line with the in vitro anticancer activity, 24c suppressed the tumor growth at a dose of 10â¯mg/kg in a MiaPaCa-2â¯cells xenograft model, but with little effect to the mice weight. Moreover, 24c strongly inhibited MiaPaCa-2â¯cell colonies formation, induced MiaPaCa-2â¯cell apoptosis, and arrested MiaPaCa-2â¯cell cycle at G2 phase. In addition, the mitochondrial bioenergetics analysis suggested that 24c could reprogram cancer cell metabolic pathways from glycolysis to oxidation phosphorylation, which verified by decreasing the extracellular acidification rates and lactate formation, and increasing oxygen consumption rate in cancer cell. All these results indicate 24c is a promising metabolic modulator for the anticancer drug development.
Subject(s)
Antineoplastic Agents/pharmacology , L-Lactate Dehydrogenase/antagonists & inhibitors , Piperazines/pharmacology , Pyrones/pharmacology , Small Molecule Libraries/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Apoptosis/drug effects , Catalytic Domain , Cell Line, Tumor , G2 Phase Cell Cycle Checkpoints/drug effects , High-Throughput Screening Assays , Humans , L-Lactate Dehydrogenase/chemistry , L-Lactate Dehydrogenase/metabolism , Mice, Nude , Mitochondria/drug effects , Molecular Docking Simulation , Oxidative Phosphorylation , Piperazines/chemical synthesis , Piperazines/chemistry , Piperazines/metabolism , Protein Binding , Pyrones/chemical synthesis , Pyrones/chemistry , Pyrones/metabolism , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/chemistry , Small Molecule Libraries/metabolism , Xenograft Model Antitumor AssaysABSTRACT
Three new ent-abietane diterpenoids, termed fischerianoids A-C (1-3), were isolated and identified from the ethyl acetate extracts of roots of the medicinally valuable plant Euphorbia fischeriana. The planar and relative structures of 1-3 were established via high-resolution electrospray ionisation mass spectrometry and one- and two-dimensional nuclear magnetic resonance spectroscopic analyses, and the absolute configuration of 1 was further established via X-ray crystallography experiment. Compounds 1-3 showed selective inhibitory potency against certain human tumor cell lines with IC50 values ranging from 8.50 ± 0.13 to 35.52 ± 0.08 µM.
