New Hydrazinothiazole Derivatives of Usnic Acid as Potent Tdp1 Inhibitors

New Hydrazinothiazole Derivatives of Usnic Acid as Potent Tdp1 Inhibitors Full article

Journal

Molecules
, E-ISSN: 1420-3049

Output data

Year: 2019, Volume: 24, Number: 20, Article number : 3711, Pages count : DOI: 10.3390/molecules24203711

Tags

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

Authors

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

Affiliations

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

Funding (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 OpenAlex

Full text from publisher

Published online:

Oct 15, 2019

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

DB	Citing
Web of science	38
Scopus	37
Elibrary	43
OpenAlex	42