Chiral Resolution, Absolute Configuration Assignment, and Genotoxicity Evaluation of Racemic 3,4-Dihydroquinazoline as a Novel Anticancer Agent

If a new drug candidate will be a mixture of enantiomers, both enantiomers should be separately studied for at least latent genotoxicity as early as possible since the thalidomide tragedy. Our group has recently reported that KCP-10043F (OZ-001) as a racemate (±)-3,4-dihydroquinazoline derivative st...

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Published inJournal of chemistry Vol. 2021; pp. 1 - 8
Main Authors Ahn, Junseong, Ko, Dohyeong, Yang, Seyoung, Moon, Kwang H., Woo, Jiwon, Yoo, Ho, Ahn, Joohoon, Lee, Jeong H., Chung, Kyung S., Lee, Kyung-T., Lee, Jae Y.
Format Journal Article
LanguageEnglish
Published New York Hindawi 25.10.2021
John Wiley & Sons, Inc
Hindawi Limited
Subjects
Ames test
Anisotropy
Anticancer properties
Apoptosis
Birth defects
Chemical reactions
Configurations
Cytotoxicity
Diastereomers
Drugs
E coli
Enantiomers
FDA approval
Genotoxicity
Hydrocarbons
Lung cancer
Metabolism
Mutation
NMR
Nuclear magnetic resonance
Pancreatic cancer
Resveratrol
Salmonella
Stereoisomerism
Thalidomide
South Korea
United States > US
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Summary:If a new drug candidate will be a mixture of enantiomers, both enantiomers should be separately studied for at least latent genotoxicity as early as possible since the thalidomide tragedy. Our group has recently reported that KCP-10043F (OZ-001) as a racemate (±)-3,4-dihydroquinazoline derivative strongly represses the proliferation of human A549 lung cancer cells by caspase-mediated apoptosis via STAT3 inactivation. To investigate the possible teratological effects of the two enantiomers of a racemic KCP-10043F, therefore chiral resolution of (±)-KCP-10043F was performed and subsequently followed by a series of chemical processes to afford the corresponding chiral diastereomers. By using 1H NMR anisotropy method, the absolute configuration (+)-KCP-10043F and (−)-KCP-10043F could be assigned as S and R configuration, respectively. The bacterial reverse mutation test (Ames test) for racemate (±)-KCP-10043F and its two enantiomers exhibited that all three stereoisomers were found to be nongenotoxic against five bacterial strains with/without metabolic activation. In addition, (R)-(−)-KCP-10043F displayed almost equal anticancer activity to (S)-(+)-KCP-10043F against three cancer cell lines. Based on these overall results, racemate KCP-10043F (OZ-001) could be used for our ongoing preclinical and clinical studies without the expensive asymmetric process and/or chiral separation.
ISSN:2090-9063
2090-9071
DOI:10.1155/2021/6169055