New inhibitors of tyrosyl-DNA phosphodiesterase I (Tdp 1) combining 7-hydroxycoumarin and monoterpenoid moieties

New inhibitors of tyrosyl-DNA phosphodiesterase I (Tdp 1) combining 7-hydroxycoumarin and monoterpenoid moieties Full article

Journal

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

Output data

Year: 2016, Volume: 24, Number: 21, Pages: 5573-5581 Pages count : 9 DOI: 10.1016/j.bmc.2016.09.016

Tags

Tyrosyl-DNA Phosphodiesterase I inhibitor; Coumarin; Monoterpene; Molecular modeling

Authors

Khomenko Tatyana ^1,4 , Zakharenko Alexandra ² , Odarchenko Tatyana ^1,4 , Arabshahi Homayon John ³ , Sannikova Victoriya ⁴ , Zakharova Olga ² , Korchagina Dina ¹ , Reynisson Johannes ³ , Volcho Konstantin ^1,4 , Salakhutdinov Nariman ^1,4 , Lavrik Olga ^2,4

Affiliations

1	(Данные Web of science) Russian Acad Sci, Siberian Branch, NN Vorozhtsov Novosibirsk Inst Organ Chem, 9 Akad Lavrentieva Ave, Novosibirsk 630090, Russia
2	(Данные Web of science) Russian Acad Sci, Siberian Branch, Novosibirsk Inst Chem Biol & Fundamental Med, 8 Akad Lavrentieva Ave, Novosibirsk 630090, Russia
3	(Данные Web of science) Univ Auckland, Sch Chem Sci, Auckland, New Zealand
4	(Данные Web of science) Novosibirsk State Univ, Pirogova 2, Novosibirsk 630090, Russia

A number of derivatives of 7-hydroxycoumarins containing aromatic or monoterpene substituents at hydroxy-group were synthesized based on a hit compound from a virtual screen. The ability of these compounds to inhibit tyrosyl-DNA phosphodiesterase I (Tdp 1), important target for anti-cancer therapy, was studied for the first time. It was found that the 7-hydroxycoumarin derivatives with monoterpene pinene moiety are effective inhibitors of Tdp 1 with the most active derivative (+)-25c with IC50 value of 0.675 mu M. This compound has low cytotoxicity (CC50 >100 mu M) when tested against human cancer cells which is crucial for presupposed application in combination with clinically established anticancer drugs. The ability of the new compounds to enhance the cytotoxicity of camptothecin, an established topoisomerase 1 poison, was demonstrated. (C) 2016 Elsevier Ltd. All rights reserved.

Khomenko T. , Zakharenko A. , Odarchenko T. , Arabshahi H.J. , Sannikova V. , Zakharova O. , Korchagina D. , Reynisson J. , Volcho K. , Salakhutdinov N. , Lavrik O.
New inhibitors of tyrosyl-DNA phosphodiesterase I (Tdp 1) combining 7-hydroxycoumarin and monoterpenoid moieties
Bioorganic and Medicinal Chemistry. 2016. V.24. N21. P.5573-5581. DOI: 10.1016/j.bmc.2016.09.016 WOS Scopus РИНЦ

Published print:

Nov 1, 2016

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