Sulfide, Sulfoxide, and Sulfone Derivatives of Usnic Acid as Inhibitors of Human TDP1 and TDP2 Enzymes

Filimonov, Aleksandr S.; Mikhailova, Marina A.; Dyrkheeva, Nadezhda S.; Chernyshova, Irina A.; Kornienko, Tatyana E.; Naumenko, Konstantin A.; Anarbaev, Rashid O.; Nefedov, Andrey A.; Achara, Chigozie; Curtis, Anthony D. M.; Luzina, Olga A.; Volcho, Konstantin P.; Salakhutdinov, Nariman F.; Lavrik, Olga I.; Reynisson, Jóhannes

Abstract

Tyrosyl-DNA phosphodiesterases 1 and 2 (TDP1 and TDP2) are important DNA repair enzymes that remove various adducts from the 3′- and 5′-ends of DNA, respectively. The suppression of the activity of these enzymes is considered as a promising adjuvant therapy for oncological diseases in combination with topoisomerase inhibitors. The simultaneous inhibition of TDP1 and TDP2 may result in greater antitumor effects, as these enzymes can mimic each other’s functions. We have previously shown that usnic acid-based sulfides can act as dual inhibitors, with TDP1 activity in the low micromolar range and their TDP2 at 1 mM. The oxidation of their sulfide moieties to sulfoxides led to an order of magnitude decrease in their cytotoxicity potential, while their TDP1 and TDP2 activity was preserved. In this work, we synthesized new series of usnic acid-based sulfides and their oxidized analogues, i.e., sulfoxides and sulfones, to systematically study these irregularities. The new compounds inhibit TDP1 with IC50 values (the concentration of inhibitor required to reduce enzyme activity by half) in the 0.33–25 μM range. Most sulfides and some sulfoxides and sulfones inhibit TDP2 with an IC50 = 138−421 μM. In addition, the most active compounds synergized (×4) with topotecan on the HeLa cell line as well as causing dose-dependent DNA damage, as confirmed by Comet assay. Sulfides with the 6-methylbenzoimidazol-2-yl substituent (8f, IC50 = 0.33/138 μM, TDP1/2) and sulfones containing a pyridine-2-yl fragment (12k, IC50 = 2/228 μM, TDP1/2) are the most potent derivatives and, therefore, are promising for further development.

Citation

Filimonov, A. S., Mikhailova, M. A., Dyrkheeva, N. S., Chernyshova, I. A., Kornienko, T. E., Naumenko, K. A., Anarbaev, R. O., Nefedov, A. A., Achara, C., Curtis, A. D. M., Luzina, O. A., Volcho, K. P., Salakhutdinov, N. F., Lavrik, O. I., & Reynisson, J. (2024). Sulfide, Sulfoxide, and Sulfone Derivatives of Usnic Acid as Inhibitors of Human TDP1 and TDP2 Enzymes. Chemistry, 6(6), 1658-1679. https://doi.org/10.3390/chemistry6060101

• Journal Article Type: Article
• Acceptance Date: Dec 4, 2024
• Online Publication Date: Dec 17, 2024
• Publication Date: Dec 17, 2024
• Deposit Date: Jan 8, 2025
• Journal: Chemistry
• Print ISSN: 2624-8549
• Electronic ISSN: 2624-8549
• Publisher: MDPI
• Peer Reviewed: Peer Reviewed
• Volume: 6
• Issue: 6
• Pages: 1658-1679
• DOI: https://doi.org/10.3390/chemistry6060101
• Public URL: https://keele-repository.worktribe.com/output/1022725