Synthesis and biological evaluation of novel tyrosyl-DNA phosphodiesterase 1 inhibitors with a benzopentathiepine moiety

Synthesis and biological evaluation of novel tyrosyl-DNA phosphodiesterase 1 inhibitors with a benzopentathiepine moiety Full article

Journal

Bioorganic and Medicinal Chemistry
ISSN: 0968-0896 , E-ISSN: 1464-3391

Output data

Year: 2015, Volume: 23, Number: 9, Pages: 2044-2052 Pages count : DOI: 10.1016/j.bmc.2015.03.020

Tags

Tyrosyl-DNA phosphodiesterase 1; TDP1; TDP1 inhibitor; Pentathiepine; Molecular modeling

Authors

Zakharenko Alexandra ¹ , Khomenko Tatyana ^2,5 , Zhukova Svetlana ³ , Koval Olga ^1,5 , Zakharova Olga ^1,3 , Anarbaev Rashid ^1,5 , Lebedeva Natalya ^1,5 , Korchagina Dina ² , Komarova Nina ² , Vasiliev Vladimir ² , Reynisson Johannes ⁴ , Volcho Konstantin ^2,5 , Salakhutdinov Nariman ^2,5 , Lavrik Olga ^1,5

Affiliations

1	(Данные Web of science) Russian Acad Sci, Novosibirsk Inst Chem Biol & Fundamental Med, Siberian Branch, Novosibirsk 630090, Russia
2	(Данные Web of science) Russian Acad Sci, NN Vorozhtsov Novosibirsk Inst Organ Chem, Siberian Branch, Novosibirsk 630090, Russia
3	(Данные Web of science) Altai State Univ, Barnaul 656049, Russia
4	(Данные Web of science) Univ Auckland, Sch Chem Sci, Auckland 1, New Zealand
5	(Данные Web of science) Novosibirsk State Univ, Novosibirsk 630090, Russia

Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a promising target for antitumor therapy based on Top1 poison-mediated DNA damage. Several novel benzopentathiepines were synthesized and tested as inhibitors of TDP1 using a new oligonucleotide-based fluorescence assay. The benzopentathiepines have IC50 values in the range of 0.2-6.0 mu M. According to the molecular modeling, the conformational flexibility of the dibutylamine group of the most effective inhibitor (3d) allows it to occupy an advantageous position for effective binding compared to its cyclic counterparts. The study of cytotoxicity of these compounds revealed that all compounds cause an apoptotic cell death in MCF-7 and Hep G2 cells. Therefore the new class of very effective inhibitors of TDP1 was elaborated. (C) 2015 Elsevier Ltd. All rights reserved.

Zakharenko A. , Khomenko T. , Zhukova S. , Koval O. , Zakharova O. , Anarbaev R. , Lebedeva N. , Korchagina D. , Komarova N. , Vasiliev V. , Reynisson J. , Volcho K. , Salakhutdinov N. , Lavrik O.
Synthesis and biological evaluation of novel tyrosyl-DNA phosphodiesterase 1 inhibitors with a benzopentathiepine moiety
Bioorganic and Medicinal Chemistry. 2015. V.23. N9. P.2044-2052. DOI: 10.1016/j.bmc.2015.03.020 WOS Scopus РИНЦ

Published print:

May 1, 2015

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