Synthesis and biological evaluation of novel tyrosyl-DNA phosphodiesterase 1 inhibitors with a benzopentathiepine moiety

Zakharenko, Alexandra; Khomenko, Tatyana; Zhukova, Svetlana; Koval, Olga; Zakharova, Olga; Anarbaev, Rashid; Lebedeva, Natalya; Korchagina, Dina; Komarova, Nina; Vasiliev, Vladimir; Reynisson, Jóhannes; Volcho, Konstantin; Salakhutdinov, Nariman; Lavrik, Olga

Abstract

Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a promising target for antitumor therapy based on Top1 poison-mediated DNA damage. Several novel benzopentathiepines were synthesized and tested as inhibitors of TDP1 using a new oligonucleotide-based fluorescence assay. The benzopentathiepines have IC50 values in the range of 0.2–6.0 μM. According to the molecular modeling, the conformational flexibility of the dibutylamine group of the most effective inhibitor (3d) allows it to occupy an advantageous position for effective binding compared to its cyclic counterparts. The study of cytotoxicity of these compounds revealed that all compounds cause an apoptotic cell death in MCF-7 and Hep G2 cells. Therefore the new class of very effective inhibitors of TDP1 was elaborated.

Citation

Zakharenko, A., Khomenko, T., Zhukova, S., Koval, O., Zakharova, O., Anarbaev, R., Lebedeva, N., Korchagina, D., Komarova, N., Vasiliev, V., Reynisson, J., Volcho, K., Salakhutdinov, N., & Lavrik, O. (2015). Synthesis and biological evaluation of novel tyrosyl-DNA phosphodiesterase 1 inhibitors with a benzopentathiepine moiety. Bioorganic and Medicinal Chemistry, 23(9), 2044-2052. https://doi.org/10.1016/j.bmc.2015.03.020

• Journal Article Type: Article
• Acceptance Date: Mar 5, 2015
• Online Publication Date: Mar 12, 2015
• Publication Date: 2015-05
• Deposit Date: Jun 13, 2023
• Journal: Bioorganic & Medicinal Chemistry
• Print ISSN: 0968-0896
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 23
• Issue: 9
• Pages: 2044-2052
• DOI: https://doi.org/10.1016/j.bmc.2015.03.020
• Keywords: Organic Chemistry; Clinical Biochemistry; Drug Discovery; Pharmaceutical Science; Molecular Biology; Molecular Medicine; Biochemistry
• Public URL: https://keele-repository.worktribe.com/output/448001
• Additional Information: This article is maintained by: Elsevier; Article Title: Synthesis and biological evaluation of novel tyrosyl-DNA phosphodiesterase 1 inhibitors with a benzopentathiepine moiety; Journal Title: Bioorganic & Medicinal Chemistry; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.bmc.2015.03.020; Content Type: article; Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.