Usnic Acid Conjugates with Monoterpenoids as Potent Tyrosyl-DNA Phosphodiesterase 1 Inhibitors

Usnic Acid Conjugates with Monoterpenoids as Potent Tyrosyl-DNA Phosphodiesterase 1 Inhibitors Научная публикация

Журнал

Journal of Natural Products
ISSN: 0163-3864

Вых. Данные

Год: 2020, Том: 83, Номер: 8, Страницы: 2320-2329 Страниц : 10 DOI: 10.1021/acs.jnatprod.9b01089

Авторы

Luzina Olga ¹ , Filimonov Alexander ^1,2 , Zakharenko Alexandra ³ , Chepanova Arina ³ , Zakharova Olga ³ , Ilina Ekateina ³ , Dyrkheeva Nadezhda ³ , Likhatskaya Galina ⁴ , Salakhutdinov Nariman ^1,2 , Lavrik Olga ^3,2

Организации

1	(Scopus) N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russian Federation
2	(Scopus) Novosibirsk State University, Novosibirsk, 630090, Russian Federation
3	(Scopus) Novosibirsk Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russian Federation
4	(Scopus) Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of Russian Academy of Sciences, Vladivostok, 690022, Russian Federation

Hybrid molecules created from different pharmacophores of natural and synthetic equivalents are successfully used in pharmaceutical practice. One promising target for anticancer therapy is tyrosyl-DNA phosphodiesterase 1 (Tdp1) because it can repair DNA lesions caused by DNA-topoisomerase 1 (Top1) inhibitors, resulting in drug resistance. In this study, new hybrid compounds were synthesized by combining the pharmacophoric moiety of a set of natural compounds with inhibitory properties against Tdp1, particularly, phenolic usnic acid and a set of different monoterpenoid fragments. These fragments were connected through a hydrazinothiazole linker. The inhibitory properties of the new compounds mainly depended on the structure of the terpenoid moieties. The two most potent compounds, 9a and 9b, were synthesized from citral and citronellal, which contain acyclic fragments with IC50 values in the range of 10-16 nM. Some synthesized derivatives showed low cytotoxicity against HeLa cells and increased the effect of the Top1 inhibitor topotecan in vitro by three to seven times. These derivatives may be considered as potential agents for the development of anticancer therapies when combined with Top1 inhibitors. Copyright © 2020 American Chemical Society and American Society of Pharmacognosy.

Luzina O. , Filimonov A. , Zakharenko A. , Chepanova A. , Zakharova O. , Ilina E. , Dyrkheeva N. , Likhatskaya G. , Salakhutdinov N. , Lavrik O.
Usnic Acid Conjugates with Monoterpenoids as Potent Tyrosyl-DNA Phosphodiesterase 1 Inhibitors
Journal of Natural Products. 2020. V.83. N8. P.2320-2329. DOI: 10.1021/acs.jnatprod.9b01089 WOS Scopus РИНЦ

Опубликована online:	28 июл. 2020 г.
Опубликована в печати:	28 авг. 2020 г.

Web of science	WOS:000566765000002
Scopus	2-s2.0-85089825639
РИНЦ	45336267
OpenAlex	W3045560418