New Hydrazinothiazole Derivatives of Usnic Acid as Potent Tdp1 Inhibitors

New Hydrazinothiazole Derivatives of Usnic Acid as Potent Tdp1 Inhibitors Научная публикация

Журнал

Molecules
, E-ISSN: 1420-3049

Вых. Данные

Год: 2019, Том: 24, Номер: 20, Номер статьи : 3711, Страниц : DOI: 10.3390/molecules24203711

Ключевые слова

tyrosyl-DNA phosphodiesterase 1 (Tdp1); topotecan; topoisomerase 1; usnic acid; molecular modeling; synergetic effect; inhibiting activity

Авторы

Filimonov Aleksander S. ^1,3 , Chepanova Arina A. ² , Luzina Olga A. ¹ , Zakharenko Alexandra L. ² , Zakharova Olga D. ² , Ilina Ekaterina S. ² , Dyrkheeva Nadezhda S. ² , Kuprushkin Maxim S. ² , Kolotaev Anton, V ⁴ , Khachatryan Derenik S. ⁴ , Patel Jinal ⁵ , Leung Ivanhoe K.H. ⁵ , Chand Raina ⁵ , Ayine-Tora Daniel M. ⁵ , Reynisson Johannes ⁶ , Volcho Konstantin P. ^1,3 , Salakhutdinov Nariman F. ^1,3 , Lavrik Olga, I ^1,3

Организации

1	(Данные Web of science) Russian Acad Sci, NN Vorozhtsov Novosibirsk Inst Organ Chem, Siberian Branch, 9 Akad Lavrentieva Ave, Novosibirsk 630090, Russia
2	(Данные Web of science) Russian Acad Sci, Novosibirsk Inst Chem Biol & Fundamental Med, Siberian Branch, 8 Akad Lavrentieva Ave, Novosibirsk 630090, Russia
3	(Данные Web of science) Novosibirsk State Univ, Pirogova Str 1, Novosibirsk 630090, Russia
4	(Данные Web of science) Natl Res Ctr, Fed State Unitary Enterprise, Inst Chem Reagents & High Pur Chem Subst, Kurchatov Inst, Moscow 107076, Russia
5	(Данные Web of science) Univ Auckland, Sch Chem Sci, Auckland 1142, New Zealand
6	(Данные Web of science) Keele Univ, Sch Pharm & Bioengn, Hornbeam Bldg, Keele ST5 5BG, Staffs, England

Информация о финансировании (1)

Российский Научный Фонд

19-13-00040

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a promising therapeutic target in cancer therapy. Combination chemotherapy using Tdp1 inhibitors as a component can potentially improve therapeutic response to many chemotherapeutic regimes. A new set of usnic acid derivatives with hydrazonothiazole pharmacophore moieties were synthesized and evaluated as Tdp1 inhibitors. Most of these compounds were found to be potent inhibitors with IC50 values in the low nanomolar range. The activity of the compounds was verified by binding experiments and supported by molecular modeling. The ability of the most effective inhibitors, used at non-toxic concentrations, to sensitize tumors to the anticancer drug topotecan was also demonstrated. The order of administration of the inhibitor and topotecan on their synergistic effect was studied, suggesting that prior or simultaneous introduction of the inhibitor with topotecan is the most effective.

Filimonov A.S. , Chepanova A.A. , Luzina O.A. , Zakharenko A.L. , Zakharova O.D. , Ilina E.S. , Dyrkheeva N.S. , Kuprushkin M.S. , Kolotaev A.V. , Khachatryan D.S. , Patel J. , Leung I.K.H. , Chand R. , Ayine-Tora D.M. , Reynisson J. , Volcho K.P. , Salakhutdinov N.F. , Lavrik O.I.
New Hydrazinothiazole Derivatives of Usnic Acid as Potent Tdp1 Inhibitors

Molecules. 2019. V.24. N20. 3711 . DOI: 10.3390/molecules24203711 WOS Scopus РИНЦ

Полный текст от издателя

Опубликована online:

15 окт. 2019 г.

Web of science	WOS:000496249500080
Scopus	2-s2.0-85073476945
РИНЦ	41649682
OpenAlex	W2980921396