Effective Inhibitors of Tyrosyl-DNA Phosphodiesterase 1 Based on Monoterpenoids as Potential Agents for Antitumor Therapy
- Authors: Chepanova A.A.1, Li-Zhulanov N.S.2,3, Sukhikh A.S.3,4, Zafar A.5, Reynisson J.6, Zakharenko A.L.1, Zakharova O.D.1, Korchagina D.V.2, Volcho K.P.2,3, Salakhutdinov N.F.2,3, Lavrik O.I.1,3
-
Affiliations:
- Institute of Chemical Biology and Fundamental Medicine, Russian Academy of Sciences
- Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences
- Novosibirsk State University
- Nikolaev Institute of Inorganic Chemistry, Siberian Branch, Russian Academy of Sciences
- School of Chemical Sciences, University of Auckland
- School of Pharmacy, Keele University, Hornbeam Building
- Issue: Vol 45, No 6 (2019)
- Pages: 647-655
- Section: Article
- URL: https://journals.rcsi.science/1068-1620/article/view/229283
- DOI: https://doi.org/10.1134/S1068162019060104
- ID: 229283
Cite item
Abstract
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 μM. Low toxicity of three compounds was shown, which makes them promising candidates for the development of accompanying cancer therapy.
About the authors
A. A. Chepanova
Institute of Chemical Biology and Fundamental Medicine, Russian Academy of Sciences
Email: lavrik@niboch.nsc.ru
Russian Federation, Novosibirsk, 630090
N. S. Li-Zhulanov
Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences; Novosibirsk State University
Email: lavrik@niboch.nsc.ru
Russian Federation, Novosibirsk, 630090; Novosibirsk, 630090
A. S. Sukhikh
Novosibirsk State University; Nikolaev Institute of Inorganic Chemistry, Siberian Branch, Russian Academy of Sciences
Email: lavrik@niboch.nsc.ru
Russian Federation, Novosibirsk, 630090; Novosibirsk, 630090
A. Zafar
School of Chemical Sciences, University of Auckland
Email: lavrik@niboch.nsc.ru
New Zealand, Auckland, 1010
J. Reynisson
School of Pharmacy, Keele University, Hornbeam Building
Email: lavrik@niboch.nsc.ru
United Kingdom, Keele, Staffordshire, ST5 5BG
A. L. Zakharenko
Institute of Chemical Biology and Fundamental Medicine, Russian Academy of Sciences
Email: lavrik@niboch.nsc.ru
Russian Federation, Novosibirsk, 630090
O. D. Zakharova
Institute of Chemical Biology and Fundamental Medicine, Russian Academy of Sciences
Email: lavrik@niboch.nsc.ru
Russian Federation, Novosibirsk, 630090
D. V. Korchagina
Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences
Email: lavrik@niboch.nsc.ru
Russian Federation, Novosibirsk, 630090
K. P. Volcho
Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences; Novosibirsk State University
Email: lavrik@niboch.nsc.ru
Russian Federation, Novosibirsk, 630090; Novosibirsk, 630090
N. F. Salakhutdinov
Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences; Novosibirsk State University
Email: lavrik@niboch.nsc.ru
Russian Federation, Novosibirsk, 630090; Novosibirsk, 630090
O. I. Lavrik
Institute of Chemical Biology and Fundamental Medicine, Russian Academy of Sciences; Novosibirsk State University
Author for correspondence.
Email: lavrik@niboch.nsc.ru
Russian Federation, Novosibirsk, 630090; Novosibirsk, 630090