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

Molecules

OlgaI. Lavrik¹  KonstantinP. Volcho²  NikolaiS. Li-Zhulanov²  NarimanF. Salakhutdinov²  AlexandraL. Zakharenko³  ArinaA. Chepanova³  Ayesha Zafar⁴  Jóhannes Reynisson⁴  Jinal Patel⁴  IvanhoeK. H. Leung⁴ 

[1] Department of Natural Sciences and Institute of Medicine and Psychology, Novosibirsk State University, Pirogova 2, Novosibirsk 630090, Russia;N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9, Akademika Lavrentieva Ave., Novosibirsk 630090, Russia;Novosibirsk Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 8, Akademika Lavrentieva Ave., Novosibirsk 630090, Russia;School of Chemical Sciences, The University of Auckland, Private Bag 92019, Victoria Street West, Auckland 1142, New Zealand;

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

DOI  :  10.3390/molecules23102468

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown