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

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

Журнал

Chemistry
ISSN: 2624-8549

Вых. Данные

Год: 2024, Том: 6, Номер: 6, Страницы: 1658-1679 Страниц : 22 DOI: 10.3390/chemistry6060101

Ключевые слова

usnic acid; sulfides; sulfoxide; sulfone; tyrosyl-DNA phosphodiesterase; TDP1 inhibitor; TDP2 inhibitor; cancer; topotecan

Авторы

Филимонов Aleksandr S. ¹ , Mikhailova Marina A. ^2,3 , Dyrkheeva Nadezhda S. ^2,3 , Chernyshova Irina A. ² , Kornienko Tatyana E. ² , Naumenko Konstantin A. ² , Anarbaev Rashid O. ² , Nefedov Andrey A. ¹ , Achara Chigozie ⁴ , Curtis Anthony D.M. ⁴ , Luzina Olga A. ¹ , Volcho Konstantin P. ¹ , Salakhutdinov Nariman F. ¹ , Lavrik Olga I. ¹ , Reynisson Jóhannes ⁴

Организации

1	N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
2	Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
3	Department of Natural Science, Novosibirsk State University, 630090 Novosibirsk, Russia
4	School of Allied Health Professions & Pharmacy, Hornbeam Building, Keele University, Staffordshire ST5 5BG, UK

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.

Филимонов 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.
Sulfide, Sulfoxide, and Sulfone Derivatives of Usnic Acid as Inhibitors of Human TDP1 and TDP2 Enzymes
Chemistry. 2024. V.6. N6. P.1658-1679. DOI: 10.3390/chemistry6060101 WOS Scopus OpenAlex

Поступила в редакцию:	3 окт. 2024 г.
Принята к публикации:	25 нояб. 2024 г.
Опубликована в печати:	17 дек. 2024 г.

Web of science:	WOS:001383766800001
Scopus:	2-s2.0-85211928898
OpenAlex:	W4405528888

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