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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Autores principales:	Junseong Ahn, Dohyeong Ko, Seyoung Yang, Kwang H. Moon, Jiwon Woo, Ho Yoo, Joohoon Ahn, Jeong H. Lee, Kyung S. Chung, Kyung-T. Lee, Jae Y. Lee
Formato:	article
Lenguaje:	EN
Publicado:	Hindawi Limited 2021
Materias:	Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/6cdb29ca810b425c8948cc86c2aa4421
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spelling	oai:doaj.org-article:6cdb29ca810b425c8948cc86c2aa44212021-11-08T02:35:33ZChiral Resolution, Absolute Configuration Assignment, and Genotoxicity Evaluation of Racemic 3,4-Dihydroquinazoline as a Novel Anticancer Agent2090-907110.1155/2021/6169055https://doaj.org/article/6cdb29ca810b425c8948cc86c2aa44212021-01-01T00:00:00Zhttp://dx.doi.org/10.1155/2021/6169055https://doaj.org/toc/2090-9071If 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.Junseong AhnDohyeong KoSeyoung YangKwang H. MoonJiwon WooHo YooJoohoon AhnJeong H. LeeKyung S. ChungKyung-T. LeeJae Y. LeeHindawi LimitedarticleChemistryQD1-999ENJournal of Chemistry, Vol 2021 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Chemistry QD1-999
spellingShingle	Chemistry QD1-999 Junseong Ahn Dohyeong Ko Seyoung Yang Kwang H. Moon Jiwon Woo Ho Yoo Joohoon Ahn Jeong H. Lee Kyung S. Chung Kyung-T. Lee Jae Y. Lee Chiral Resolution, Absolute Configuration Assignment, and Genotoxicity Evaluation of Racemic 3,4-Dihydroquinazoline as a Novel Anticancer Agent
description	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.
format	article
author	Junseong Ahn Dohyeong Ko Seyoung Yang Kwang H. Moon Jiwon Woo Ho Yoo Joohoon Ahn Jeong H. Lee Kyung S. Chung Kyung-T. Lee Jae Y. Lee
author_facet	Junseong Ahn Dohyeong Ko Seyoung Yang Kwang H. Moon Jiwon Woo Ho Yoo Joohoon Ahn Jeong H. Lee Kyung S. Chung Kyung-T. Lee Jae Y. Lee
author_sort	Junseong Ahn
title	Chiral Resolution, Absolute Configuration Assignment, and Genotoxicity Evaluation of Racemic 3,4-Dihydroquinazoline as a Novel Anticancer Agent
title_short	Chiral Resolution, Absolute Configuration Assignment, and Genotoxicity Evaluation of Racemic 3,4-Dihydroquinazoline as a Novel Anticancer Agent
title_full	Chiral Resolution, Absolute Configuration Assignment, and Genotoxicity Evaluation of Racemic 3,4-Dihydroquinazoline as a Novel Anticancer Agent
title_fullStr	Chiral Resolution, Absolute Configuration Assignment, and Genotoxicity Evaluation of Racemic 3,4-Dihydroquinazoline as a Novel Anticancer Agent
title_full_unstemmed	Chiral Resolution, Absolute Configuration Assignment, and Genotoxicity Evaluation of Racemic 3,4-Dihydroquinazoline as a Novel Anticancer Agent
title_sort	chiral resolution, absolute configuration assignment, and genotoxicity evaluation of racemic 3,4-dihydroquinazoline as a novel anticancer agent
publisher	Hindawi Limited
publishDate	2021
url	https://doaj.org/article/6cdb29ca810b425c8948cc86c2aa4421
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Chiral Resolution, Absolute Configuration Assignment, and Genotoxicity Evaluation of Racemic 3,4-Dihydroquinazoline as a Novel Anticancer Agent

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