New inhibitors of tyrosyl-DNA phosphodiesterase I (Tdp 1) combining 7-hydroxycoumarin and monoterpenoid moieties

Khomenko, Tatyana; Zakharenko, Alexandra; Odarchenko, Tatyana; Arabshahi, Homayon John; Sannikova, Victoriya; Zakharova, Olga; Korchagina, Dina; Reynisson, Jóhannes; Volcho, Konstantin; Salakhutdinov, Nariman; Lavrik, Olga

Abstract

A number of derivatives of 7-hydroxycoumarins containing aromatic or monoterpene substituents at hydroxy-group were synthesized based on a hit compound from a virtual screen. The ability of these compounds to inhibit tyrosyl-DNA phosphodiesterase I (Tdp 1), important target for anti-cancer therapy, was studied for the first time. It was found that the 7-hydroxycoumarin derivatives with monoterpene pinene moiety are effective inhibitors of Tdp 1 with the most active derivative (+)-25c with IC50 value of 0.675 μM. This compound has low cytotoxicity (CC50 >100 μM) when tested against human cancer cells which is crucial for presupposed application in combination with clinically established anticancer drugs. The ability of the new compounds to enhance the cytotoxicity of camptothecin, an established topoisomerase 1 poison, was demonstrated.

Citation

Khomenko, T., Zakharenko, A., Odarchenko, T., Arabshahi, H. J., Sannikova, V., Zakharova, O., …Lavrik, O. (2016). New inhibitors of tyrosyl-DNA phosphodiesterase I (Tdp 1) combining 7-hydroxycoumarin and monoterpenoid moieties. Bioorganic and Medicinal Chemistry, 24(21), 5573-5581. https://doi.org/10.1016/j.bmc.2016.09.016

• Journal Article Type: Article
• Acceptance Date: Sep 8, 2016
• Online Publication Date: Sep 9, 2016
• Publication Date: 2016-11
• Deposit Date: Jun 12, 2023
• Journal: Bioorganic & Medicinal Chemistry
• Print ISSN: 0968-0896
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 24
• Issue: 21
• Pages: 5573-5581
• DOI: https://doi.org/10.1016/j.bmc.2016.09.016
• Keywords: Organic Chemistry; Clinical Biochemistry; Drug Discovery; Pharmaceutical Science; Molecular Biology; Molecular Medicine; Biochemistry; Tyrosyl-DNA Phosphodiesterase I inhibitor; Coumarin; Monoterpene; Molecular modeling
• Additional Information: This article is maintained by: Elsevier; Article Title: New inhibitors of tyrosyl-DNA phosphodiesterase I (Tdp 1) combining 7-hydroxycoumarin and monoterpenoid moieties; Journal Title: Bioorganic & Medicinal Chemistry; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.bmc.2016.09.016; Content Type: article; Copyright: © 2016 Elsevier Ltd. All rights reserved.