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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Hindawi Limited
2021-01-01
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| Series: | Journal of Chemistry |
| Online Access: | http://dx.doi.org/10.1155/2021/6169055 |
| _version_ | 1826998385842847744 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-11T20:01:17Z |
| format | Article |
| id | doaj.art-6cdb29ca810b425c8948cc86c2aa4421 |
| institution | Directory Open Access Journal |
| issn | 2090-9063 2090-9071 |
| language | English |
| last_indexed | 2025-02-18T10:14:20Z |
| publishDate | 2021-01-01 |
| publisher | Hindawi Limited |
| record_format | Article |
| series | Journal of Chemistry |
| spelling | doaj.art-6cdb29ca810b425c8948cc86c2aa44212024-11-02T05:32:34ZengHindawi LimitedJournal of Chemistry2090-90632090-90712021-01-01202110.1155/2021/61690556169055Chiral Resolution, Absolute Configuration Assignment, and Genotoxicity Evaluation of Racemic 3,4-Dihydroquinazoline as a Novel Anticancer AgentJunseong Ahn0Dohyeong Ko1Seyoung Yang2Kwang H. Moon3Jiwon Woo4Ho Yoo5Joohoon Ahn6Jeong H. Lee7Kyung S. Chung8Kyung-T. Lee9Jae Y. Lee10Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul 02447, Republic of KoreaResearch Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul 02447, Republic of KoreaResearch Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul 02447, Republic of KoreaResearch Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul 02447, Republic of KoreaResearch Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul 02447, Republic of KoreaONCOZEN Co.,Ltd., ONCOZEN R&D Center, C-713, Beobwon-ro 11-gil, Songpa-gu, Seoul 05836, Republic of KoreaONCOZEN Co.,Ltd., ONCOZEN R&D Center, C-713, Beobwon-ro 11-gil, Songpa-gu, Seoul 05836, Republic of KoreaDepartment of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of KoreaDepartment of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of KoreaDepartment of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of KoreaResearch Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul 02447, Republic of KoreaIf 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.http://dx.doi.org/10.1155/2021/6169055 |
| spellingShingle | 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 Journal of Chemistry |
| title | 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_short | 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 |
| url | http://dx.doi.org/10.1155/2021/6169055 |
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