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The synthesis of furoquinolinedione and isoxazoloquinolinedione derivatives as selective Tyrosyl-DNA phosphodiesterase 2 (TDP2) inhibitors.

ABSTRACT: Based on our previous study on the development of the furoquinolinedione and isoxazoloquinolinedione TDP2 inhibitors, the further structure-activity relationship (SAR) was studied in this work. A series of furoquinolinedione and isoxazoloquinolinedione derivatives were synthesized and tested for enzyme inhibitions. Enzyme-based assays indicated that isoxazoloquinolinedione derivatives selectively showed high TDP2 inhibitory activity at sub-micromolar range, as well as furoquinolinedione derivatives at low micromolar range. The most potent 3-(3,4-dimethoxyphenyl)isoxazolo[4,5-g]quinoline-4,9-dione (70) showed TDP2 inhibitory activity with IC₅₀ of 0.46 ± 0.15 μM. This work will facilitate future efforts for the discovery of isoxazoloquinolinedione TDP2 selective inhibitors.

SUBMITTER: Yang H

PROVIDER: S-EPMC9893515 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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The synthesis of furoquinolinedione and isoxazoloquinolinedione derivatives as selective Tyrosyl-DNA phosphodiesterase 2 (TDP2) inhibitors.

Yang Hao H Zhu Xiao-Qing XQ Wang Wenjie W Chen Yu Y Hu Zhu Z Zhang Yu Y Hu De-Xuan DX Yu Le-Mao LM Agama Keli K Pommier Yves Y An Lin-Kun LK

Bioorganic chemistry 20210401

Based on our previous study on the development of the furoquinolinedione and isoxazoloquinolinedione TDP2 inhibitors, the further structure-activity relationship (SAR) was studied in this work. A series of furoquinolinedione and isoxazoloquinolinedione derivatives were synthesized and tested for enzyme inhibitions. Enzyme-based assays indicated that isoxazoloquinolinedione derivatives selectively showed high TDP2 inhibitory activity at sub-micromolar range, as well as furoquinolinedione derivati ...[more]

PMID: 33839584

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