Effective Inhibitors of Tyrosyl-DNA Phosphodiesterase 1 Based on Monoterpenoids as Potential Agents for Antitumor Therapy

Effective Inhibitors of Tyrosyl-DNA Phosphodiesterase 1 Based on Monoterpenoids as Potential Agents for Antitumor Therapy Full article

Journal

Russian Journal of Bioorganic Chemistry
ISSN: 1068-1620

Output data

Year: 2019, Volume: 45, Number: 6, Pages: 647-655 Pages count : 9 DOI: 10.1134/S1068162019060104

Tags

tyrosyl-DNA phosphodiesterase 1 inhibitors; topotecan; octahydro-2H-chromene; cytotoxicity

Authors

Chepanova A.A. ¹ , Li-Zhulanov N.S. ^2,3 , Sukhikh A.S. ^3,6 , Zafar A. ⁴ , Reynisson J. ⁵ , Zakharenko A.L. ¹ , Zakharova O.D. ¹ , Korchagina D., V ² , Voleho K.P. ^2,3 , Salakhutdinov N.F. ^2,3 , Lavrik O., I ^1,3

Affiliations

1	(Данные Web of science) Russian Acad Sci, Inst Chem Biol & Fundamental Med, Novosibirsk 630090, Russia
2	(Данные Web of science) Russian Acad Sci, Vorozhtsov Novosibirsk Inst Organ Chem, Siberian Branch, Novosibirsk 630090, Russia
3	(Данные Web of science) Novosibirsk State Univ, Novosibirsk 630090, Russia
4	(Данные Web of science) Univ Auckland, Sch Chem Sci, Auckland 1010, New Zealand
5	(Данные Web of science) Keele Univ, Sch Pharm, Hornbeam Bldg, Keele ST5 5BG, Staffs, England
6	(Данные Web of science) Russian Acad Sci, Nikolaev Inst Inorgan Chem, Siberian Branch, Novosibirsk 630090, Russia

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is one of the important DNA repair enzymes responsible for the repair of DNA damage caused by anticancer drugs, such as topotecan. In this regard, enzyme activity is one of the possible causes of tumor resistance to chemotherapy, and the use of inhibitors of this enzyme is considered as a promising adjuvant therapy. We have obtained a number of new isomeric naphthyl derivatives of thiophenyl octahydro-2H-chromene, the structure of one of which is confirmed by X-ray structural analysis. Based on molecular modeling data, the structure of the ligand-Tdp1 complex has been proposed. All compounds obtained inhibit Tdp1 at a concentration of about 2 mu M. Low toxicity of three compounds was shown, which makes them promising candidates for the development of accompanying cancer therapy.

Chepanova A.A. , Li-Zhulanov N.S. , Sukhikh A.S. , Zafar A. , Reynisson J. , Zakharenko A.L. , Zakharova O.D. , Korchagina D.,.V. , Voleho K.P. , Salakhutdinov N.F. , Lavrik O.,.I.
Effective Inhibitors of Tyrosyl-DNA Phosphodiesterase 1 Based on Monoterpenoids as Potential Agents for Antitumor Therapy
Russian Journal of Bioorganic Chemistry. 2019. V.45. N6. P.647-655. DOI: 10.1134/S1068162019060104 WOS Scopus РИНЦ

Published print:	Nov 1, 2019
Published online:	Jan 16, 2020

Web of science	WOS:000520225900024
Scopus	2-s2.0-85077900104
Elibrary	43242193
OpenAlex	W2999831906