Arylazopyrazole-Based Photoswitchable Inhibitors Selective for Dihydrofolate Reductase.

Selective inhibitors of 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, . Substitution of the skeletal -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.