Arylazopyrazole-Based Photoswitchable Inhibitors Selective for Escherichia coli Dihydrofolate Reductase

Selective inhibitors of Escherichia coli dihydrofolate reductase (eDHFR) are crucial chemical biology tools that have widespread clinical applications. We developed a set of eDHFR-selective photoswitchable inhibitors by derivatizing the structure of our previously reported methotrexate (MTX) azolog,...

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Bibliographic Details
Published in:ACS chemical biology 2023-02, Vol.18 (2), p.340-346
Main Authors: Sarkar, Himadri S., Mashita, Takato, Kowada, Toshiyuki, Hamaguchi, Satoshi, Sato, Toshizo, Kasahara, Kento, Matubayasi, Nobuyuki, Matsui, Toshitaka, Mizukami, Shin
Format: Article
Language:English
Subjects:
Escherichia coli
Humans
Methotrexate - chemistry
Methotrexate - pharmacology
Tetrahydrofolate Dehydrogenase - chemistry
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Summary:Selective inhibitors of Escherichia coli dihydrofolate reductase (eDHFR) are crucial chemical biology tools that have widespread clinical applications. We developed a set of eDHFR-selective photoswitchable inhibitors by derivatizing the structure of our previously reported methotrexate (MTX) azolog, azoMTX. Substitution of the skeletal p-phenylene group of azoMTX with bulky bis-alkylated arylazopyrazole moieties significantly increased its selectivity toward eDHFR over human DHFR. Owing to the physical properties of arylazopyrazoles, the new ligands exhibited nearly complete Z-to-E photoconversion and high thermostability of Z-isomers. In addition, real-time photoreversible control of eDHFR activity was achieved by alternatively switching the illumination light wavelengths.
ISSN:1554-8929
1554-8937
DOI:10.1021/acschembio.2c00749