A Novel Class of Tyrosyl-DNA Phosphodiesterase 1 Inhibitors That Contains the Octahydro-2H-chromen-4-ol Scaffold

A Novel Class of Tyrosyl-DNA Phosphodiesterase 1 Inhibitors That Contains the Octahydro-2H-chromen-4-ol Scaffold Full article

Journal

Molecules
, E-ISSN: 1420-3049

Output data

Year: 2018, Volume: 23, Number: 10, Article number : 2468, Pages count : DOI: 10.3390/molecules23102468

Tags

anticancer agent; Tdp1 inhibitor; DNA repair enzyme; synthesis; biochemical assay; molecular modeling; chemical space; structural-activity relationships

Authors

Li-Zhulanov Nikolai S. ^1,2,3 , Zakharenko Alexandra L. ⁴ , Chepanova Arina A. ⁴ , Patel Jinal ⁵ , Zafar Ayesha ⁵ , Volcho Konstantin P. ^1,2,3 , Salakhutdinov Nariman F. ^1,2,3 , Reynisson Johannes ⁵ , Leung Ivanhoe K.H. ⁵ , Lavrik Olga I. ^2,3,4

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) Novosibirsk State Univ, Dept Nat Sci, Pirogova 2, Novosibirsk 630090, Russia
3	(Данные Web of science) Novosibirsk State Univ, Inst Med & Psychol, Pirogova 2, Novosibirsk 630090, Russia
4	(Данные Web of science) Russian Acad Sci, Novosibirsk Inst Chem Biol & Fundamental Med, Siberian Branch, 8 Akad Lavrentieva Ave, Novosibirsk 630090, Russia
5	(Данные Web of science) Univ Auckland, Sch Chem Sci, Private Bag 92019,Victoria St West, Auckland 1142, New Zealand

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a DNA repair enzyme that mends topoisomerase 1-mediated DNA damage. Tdp1 is a current inhibition target for the development of improved anticancer treatments, as its inhibition may enhance the therapeutic effect of topoisomerase 1 poisons. Here, we report a study on the development of a novel class of Tdp1 inhibitors that is based on the octahydro-2H-chromene scaffold. Inhibition and binding assays revealed that these compounds are potent inhibitors of Tdp1, with IC50 and K-D values in the low micromolar concentration range. Molecular modelling predicted plausible conformations of the active ligands, blocking access to the enzymatic machinery of Tdp1. Our results thus help establish a structural-activity relationship for octahydro-2H-chromene-based Tdp1 inhibitors, which will be useful for future Tdp1 inhibitor development work.

Li-Zhulanov N.S. , Zakharenko A.L. , Chepanova A.A. , Patel J. , Zafar A. , Volcho K.P. , Salakhutdinov N.F. , Reynisson J. , Leung I.K.H. , Lavrik O.I.
A Novel Class of Tyrosyl-DNA Phosphodiesterase 1 Inhibitors That Contains the Octahydro-2H-chromen-4-ol Scaffold

Molecules. 2018. V.23. N10. 2468 . DOI: 10.3390/molecules23102468 WOS Scopus РИНЦ

Full text from publisher

Published online:

Sep 26, 2018

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