Synthesis and initial screening of lactate dehydrogenase inhibitor activity of 1,3-benzodioxole derivatives

Cancer is one of the main causes of mortality in the world. Many cancer cells produce ATP through high-level lactic acid fermentation catalyzed by lactate dehydrogenase (LDH), which converts pyruvic acid to lactic acid. LDH plays a dominant role in the Warburg effect, wherein aerobic glycolysis is f...

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Published in:Scientific reports 2020-11, Vol.10 (1), p.19889-19889, Article 19889
Main Authors: Annas, Dicky, Cheon, Se-Yun, Yusuf, Mohammad, Bae, Sung-Jin, Ha, Ki-Tae, Park, Kang Hyun
Format: Article
Language:English
Subjects:
Acid production
Acids
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - pharmacology
Cancer
Cell Proliferation
Cytotoxicity
Dehydrogenases
Dioxoles - chemistry
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - pharmacology
Esterification
Fermentation
Glycolysis
Humans
L-Lactate dehydrogenase
L-Lactate Dehydrogenase - antagonists & inhibitors
Lactic acid
Neoplasms - drug therapy
Neoplasms - enzymology
Neoplasms - pathology
Oxidative phosphorylation
Pancreatic cancer
Phosphorylation
Pyruvic acid
Tumor Cells, Cultured
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Summary:Cancer is one of the main causes of mortality in the world. Many cancer cells produce ATP through high-level lactic acid fermentation catalyzed by lactate dehydrogenase (LDH), which converts pyruvic acid to lactic acid. LDH plays a dominant role in the Warburg effect, wherein aerobic glycolysis is favored over oxidative phosphorylation. Due to the high lactic acid production level in cancer cells, LDH-targeting could be a potential cancer treatment strategy. A few approaches, such as drug treatment, reportedly inhibited LDH activity. In this study, we describe new 1,3-benzodioxole derivatives that might be potential small molecule candidates for LDHA inhibition. The synthesis was carried out by trans-esterification between aryl ester and alcohol groups from piperonyl alcohol. Compounds 2 and 10 exhibited a selective LDHA IC value of 13.63 µM and 47.2 µM, respectively. Whereas only compound 10 showed significant cytotoxicity in several lines of cancer cells, especially in human pancreatic cancer PANC-1 cells. These synthesized compounds possess 2 aromatic rings and -CF moiety, which expectedly contributes to LDHA inhibition. The presented products have the potential to become a promising LDHA inhibitor drug candidate.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-020-77056-4