Egemen Foto1, Çigdem Özen2, Fatma Zilifdar3, Betül Tekiner-Gülbaş4, İlkay Yıldız4, Esin Akı-Yalçın4, Nuran Diril3, İsmail Yalçın4. 1. Department of Biotechnology, Faculty of Science, Necmettin Erbakan University, Konya, Turkey. egemenfoto@yahoo.com. 2. Izmir International Biomedicine and Genome Institute, iBG-izmir, Dokuz Eylül University, Izmir, Turkey. 3. Department of Molecular Biology, Faculty of Science, Hacettepe University, Ankara, Turkey. 4. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, Ankara, Turkey.
Abstract
BACKGROUND: The numbers of topoisomerase I targeted drugs on the market are very limited although they are used clinically for treatment of solid tumors. Hence, studies about finding new chemical structures which specifically target topoisomerase I are still remarkable. OBJECTIVES: In this present study, we tested previously synthesized 3,4-dihydro-2H-1,4-benzoxazin-3-one derivatives to reveal their human DNA topoisomerase I inhibitory potentials. METHODS: We investigated inhibitory activities of 3,4-dihydro-2H-1,4-benzoxazin-3-one derivatives on human topoisomerase I by relaxation assay to clarify inhibition mechanisms of effective derivatives with EMSA and T4 DNA ligase based intercalation assay. With SAR study, it was tried to find out effective groups in the ring system. RESULTS: While 10 compounds showed catalytic inhibitory activity, 8 compounds were found to be potential topoisomerase poisons. 4 of them also exhibited both activities. 2-hydroxy-3,4-dihydro-2H-1,4-benzoxazin-3-one (BONC-001) was the most effective catalytic inhibitor (IC50:8.34 mM) and ethyl 6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-acetate (BONC-013) was the strongest potential poison (IC50:0.0006 mM). BONC-013 was much more poisonous than camptothecin (IC50:0.034 mM). Intercalation assay showed that BONC-013 was not an intercalator and BONC-001 most probably prevented enzyme-substrate binding in an unknown way. Another important result of this study was that OH group instead of ethoxycarbonylmethyl group at R position of benzoxazine ring was important for hTopo I catalytic inhibition while the attachment of a methyl group of R1 position at R2 position were play a role for increasing of its poisonous effect. CONCLUSION: As a result, we presented new DNA topoisomerase I inhibitors which might serve novel constructs for future anticancer agent designs. Graphical abstract.
BACKGROUND: The numbers of topoisomerase I targeted drugs on the market are very limited although they are used clinically for treatment of solid tumors. Hence, studies about finding new chemical structures which specifically target topoisomerase I are still remarkable. OBJECTIVES: In this present study, we tested previously synthesized 3,4-dihydro-2H-1,4-benzoxazin-3-one derivatives to reveal their human DNA topoisomerase I inhibitory potentials. METHODS: We investigated inhibitory activities of 3,4-dihydro-2H-1,4-benzoxazin-3-one derivatives on human topoisomerase I by relaxation assay to clarify inhibition mechanisms of effective derivatives with EMSA and T4 DNA ligase based intercalation assay. With SAR study, it was tried to find out effective groups in the ring system. RESULTS: While 10 compounds showed catalytic inhibitory activity, 8 compounds were found to be potential topoisomerase poisons. 4 of them also exhibited both activities. 2-hydroxy-3,4-dihydro-2H-1,4-benzoxazin-3-one (BONC-001) was the most effective catalytic inhibitor (IC50:8.34 mM) and ethyl 6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-acetate (BONC-013) was the strongest potential poison (IC50:0.0006 mM). BONC-013 was much more poisonous than camptothecin (IC50:0.034 mM). Intercalation assay showed that BONC-013 was not an intercalator and BONC-001 most probably prevented enzyme-substrate binding in an unknown way. Another important result of this study was that OH group instead of ethoxycarbonylmethyl group at R position of benzoxazine ring was important for hTopo I catalytic inhibition while the attachment of a methyl group of R1 position at R2 position were play a role for increasing of its poisonous effect. CONCLUSION: As a result, we presented new DNA topoisomerase I inhibitors which might serve novel constructs for future anticancer agent designs. Graphical abstract.
Entities:
Keywords:
Anticancer; Benzoxazine; Catalytic inhibitor; Topoisomerase I; Topoisomerase I poison
Authors: S Alper-Hayta; E Aki-Sener; B Tekiner-Gulbas; I Yildiz; O Temiz-Arpaci; I Yalcin; N Altanlar Journal: Eur J Med Chem Date: 2006-09-22 Impact factor: 6.514
Authors: Justine L Delgado; Sarah R C Lentz; Chaitanya A Kulkarni; Pratik R Chheda; Hailey A Held; Hiroshi Hiasa; Robert J Kerns Journal: Eur J Med Chem Date: 2019-03-20 Impact factor: 6.514
Authors: Jiu Hong Wu; Fang Rong Chang; Ken ichiro Hayashi; Hiroaki Shiraki; Chih Chuang Liaw; Yuka Nakanishi; Kenneth F Bastow; Donglei Yu; Ih Sheng Chen; Kuo Hsiung Lee Journal: Bioorg Med Chem Lett Date: 2003-07-07 Impact factor: 2.823
Authors: KirkE Hevener; Tatsiana A Verstak; Katie E Lutat; Daniel L Riggsbee; Jeremiah W Mooney Journal: Acta Pharm Sin B Date: 2018-07-25 Impact factor: 11.413