A Novel Class of Tyrosyl-DNA Phosphodiesterase 1 Inhibitors That Contains the Octahydro-2H-chromen-4-ol Scaffold
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...
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MDPI AG
2018-09-01
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| Series: | Molecules |
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| Online Access: | http://www.mdpi.com/1420-3049/23/10/2468 |
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doaj-bc1d0fabb83c40fb89ffb6afba87a9552020-11-25T02:27:30ZengMDPI AGMolecules1420-30492018-09-012310246810.3390/molecules23102468molecules23102468A Novel Class of Tyrosyl-DNA Phosphodiesterase 1 Inhibitors That Contains the Octahydro-2H-chromen-4-ol ScaffoldNikolai S. Li-Zhulanov0Alexandra L. Zakharenko1Arina A. Chepanova2Jinal Patel3Ayesha Zafar4Konstantin P. Volcho5Nariman F. Salakhutdinov6Jóhannes Reynisson7Ivanhoe K. H. Leung8Olga I. Lavrik9N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9, Akademika Lavrentieva Ave., Novosibirsk 630090, RussiaNovosibirsk Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 8, Akademika Lavrentieva Ave., Novosibirsk 630090, RussiaNovosibirsk Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 8, Akademika Lavrentieva Ave., Novosibirsk 630090, RussiaSchool of Chemical Sciences, The University of Auckland, Private Bag 92019, Victoria Street West, Auckland 1142, New ZealandSchool of Chemical Sciences, The University of Auckland, Private Bag 92019, Victoria Street West, Auckland 1142, New ZealandN. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9, Akademika Lavrentieva Ave., Novosibirsk 630090, RussiaN. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9, Akademika Lavrentieva Ave., Novosibirsk 630090, RussiaSchool of Chemical Sciences, The University of Auckland, Private Bag 92019, Victoria Street West, Auckland 1142, New ZealandSchool of Chemical Sciences, The University of Auckland, Private Bag 92019, Victoria Street West, Auckland 1142, New ZealandDepartment of Natural Sciences and Institute of Medicine and Psychology, Novosibirsk State University, Pirogova 2, Novosibirsk 630090, RussiaTyrosyl-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.http://www.mdpi.com/1420-3049/23/10/2468anticancer agentTdp1 inhibitorDNA repair enzymesynthesisbiochemical assaymolecular modelingchemical spacestructural-activity relationships |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Nikolai S. Li-Zhulanov Alexandra L. Zakharenko Arina A. Chepanova Jinal Patel Ayesha Zafar Konstantin P. Volcho Nariman F. Salakhutdinov Jóhannes Reynisson Ivanhoe K. H. Leung Olga I. Lavrik |
| spellingShingle |
Nikolai S. Li-Zhulanov Alexandra L. Zakharenko Arina A. Chepanova Jinal Patel Ayesha Zafar Konstantin P. Volcho Nariman F. Salakhutdinov Jóhannes Reynisson Ivanhoe K. H. Leung Olga I. Lavrik A Novel Class of Tyrosyl-DNA Phosphodiesterase 1 Inhibitors That Contains the Octahydro-2H-chromen-4-ol Scaffold Molecules anticancer agent Tdp1 inhibitor DNA repair enzyme synthesis biochemical assay molecular modeling chemical space structural-activity relationships |
| author_facet |
Nikolai S. Li-Zhulanov Alexandra L. Zakharenko Arina A. Chepanova Jinal Patel Ayesha Zafar Konstantin P. Volcho Nariman F. Salakhutdinov Jóhannes Reynisson Ivanhoe K. H. Leung Olga I. Lavrik |
| author_sort |
Nikolai S. Li-Zhulanov |
| title |
A Novel Class of Tyrosyl-DNA Phosphodiesterase 1 Inhibitors That Contains the Octahydro-2H-chromen-4-ol Scaffold |
| title_short |
A Novel Class of Tyrosyl-DNA Phosphodiesterase 1 Inhibitors That Contains the Octahydro-2H-chromen-4-ol Scaffold |
| title_full |
A Novel Class of Tyrosyl-DNA Phosphodiesterase 1 Inhibitors That Contains the Octahydro-2H-chromen-4-ol Scaffold |
| title_fullStr |
A Novel Class of Tyrosyl-DNA Phosphodiesterase 1 Inhibitors That Contains the Octahydro-2H-chromen-4-ol Scaffold |
| title_full_unstemmed |
A Novel Class of Tyrosyl-DNA Phosphodiesterase 1 Inhibitors That Contains the Octahydro-2H-chromen-4-ol Scaffold |
| title_sort |
novel class of tyrosyl-dna phosphodiesterase 1 inhibitors that contains the octahydro-2h-chromen-4-ol scaffold |
| publisher |
MDPI AG |
| series |
Molecules |
| issn |
1420-3049 |
| publishDate |
2018-09-01 |
| description |
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. |
| topic |
anticancer agent Tdp1 inhibitor DNA repair enzyme synthesis biochemical assay molecular modeling chemical space structural-activity relationships |
| url |
http://www.mdpi.com/1420-3049/23/10/2468 |
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