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Article

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

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N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9, Akademika Lavrentieva Ave., Novosibirsk 630090, Russia
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Department of Natural Sciences and Institute of Medicine and Psychology, Novosibirsk State University, Pirogova 2, Novosibirsk 630090, Russia
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Novosibirsk Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 8, Akademika Lavrentieva Ave., Novosibirsk 630090, Russia
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School of Chemical Sciences, The University of Auckland, Private Bag 92019, Victoria Street West, Auckland 1142, New Zealand
*
Authors to whom correspondence should be addressed.
Molecules 2018, 23(10), 2468; https://doi.org/10.3390/molecules23102468
Received: 4 September 2018 / Revised: 21 September 2018 / Accepted: 22 September 2018 / Published: 26 September 2018
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 KD 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. View Full-Text
Keywords: anticancer agent; Tdp1 inhibitor; DNA repair enzyme; synthesis; biochemical assay; molecular modeling; chemical space; structural-activity relationships anticancer agent; Tdp1 inhibitor; DNA repair enzyme; synthesis; biochemical assay; molecular modeling; chemical space; structural-activity relationships
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MDPI and ACS Style

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, 23, 2468. https://doi.org/10.3390/molecules23102468

AMA Style

Li-Zhulanov NS, Zakharenko AL, Chepanova AA, Patel J, Zafar A, Volcho KP, Salakhutdinov NF, Reynisson J, Leung IKH, Lavrik OI. A Novel Class of Tyrosyl-DNA Phosphodiesterase 1 Inhibitors That Contains the Octahydro-2H-chromen-4-ol Scaffold. Molecules. 2018; 23(10):2468. https://doi.org/10.3390/molecules23102468

Chicago/Turabian Style

Li-Zhulanov, Nikolai S.; Zakharenko, Alexandra L.; Chepanova, Arina A.; Patel, Jinal; Zafar, Ayesha; Volcho, Konstantin P.; Salakhutdinov, Nariman F.; Reynisson, Jóhannes; Leung, Ivanhoe K.H.; Lavrik, Olga I. 2018. "A Novel Class of Tyrosyl-DNA Phosphodiesterase 1 Inhibitors That Contains the Octahydro-2H-chromen-4-ol Scaffold" Molecules 23, no. 10: 2468. https://doi.org/10.3390/molecules23102468

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