1. Synthesis, biological evaluation and structure-activity relationship of novel dichloroacetophenones targeting pyruvate dehydrogenase kinases with potent anticancer activity.
- Author
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Xu B, Wang ZP, Liu Q, Yang X, Li X, Huang D, Qiu Y, Tam KY, Zhang SL, and He Y
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Apoptosis drug effects, Cell Proliferation drug effects, Cell Survival drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Molecular Structure, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Pyruvate Dehydrogenase Acetyl-Transferring Kinase metabolism, Structure-Activity Relationship, Tumor Cells, Cultured, omega-Chloroacetophenone chemical synthesis, omega-Chloroacetophenone chemistry, Antineoplastic Agents pharmacology, Protein Kinase Inhibitors pharmacology, Pyruvate Dehydrogenase Acetyl-Transferring Kinase antagonists & inhibitors, omega-Chloroacetophenone pharmacology
- Abstract
Pyruvate dehydrogenase kinases (PDKs) are promising therapeutic targets that have received increasing attentions in cancer metabolism. In this paper, we report the synthesis and biological evaluation of a series of novel dichloroacetophenones as potent PDKs inhibitors. Structure-activity relationship analysis enabled us to identify a potent compound 6u, which inhibited PDKs with an EC
50 value of 0.09 μM, and reduced various cancer cells proliferation with IC50 values ranging from 1.1 to 3.8 μM, while show weak effect against non-cancerous L02 cell (IC50 > 10 μM). In the A375 xenograft model, 6u displayed an obvious antitumor activity at a dose of 5 mg/kg, but with no negative effect to the mice weight. Molecular docking suggested that 6u formed direct hydrogen bond interactions with Ser75 and Gln61 in PDK1, and meanwhile the aniline skeleton in 6u was sandwiched by the conserved hydrophobic residues Phe78 and Phe65, which contribute to the biochemical activity improvement. Moreover, 6u induced A375 cell apoptosis and cell arrest in G1 phase, and inhibited cancer cell migration. In addition, 6u altered glucose metabolic pathway in A375 cell by decreasing lactate formation and increasing ROS production and OCR consumption, which could serve as a potential modulator to reprogram the glycolysis pathway in cancer cell., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)- Published
- 2021
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