Arylazopyrazole-Based Photoswitchable Inhibitors Selective for Escherichia coli Dihydrofolate Reductase

Abstract

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.

Azoheteroarene and Diazocine Molecular Photoswitches: Self‐Assembly, Responsive Materials and Photopharmacology

“…[62] In a recent report, Mizukami and co-workers used an AAP derivative as a selective inhibitor towards Escherichia coli dihydrofolate reductase (eDHFR) in comparison to human DHFR (hDHFR) (Figure 3e). [63] The efficient photopharmacophore analogues of methotrexate (MTX, a known DHFR inhibitor) allowed photocontrollable inhibition activity with 50 times higher binding affinity compared to the AB analogue. [63] AAP derivatives can also function as a photoswitchable antagonistic for Vertebrate TRPA1 Channel as reported by the group of Peterson and Fuchter (Figure 3e).…”

“…[63] The efficient photopharmacophore analogues of methotrexate (MTX, a known DHFR inhibitor) allowed photocontrollable inhibition activity with 50 times higher binding affinity compared to the AB analogue. [63] AAP derivatives can also function as a photoswitchable antagonistic for Vertebrate TRPA1 Channel as reported by the group of Peterson and Fuchter (Figure 3e). [64] Gorostiza and co-workers achieved on-demand modulation of adrenergic neurotransmission by using dichloro substituted AAP derivatives which controlled the pupil response in mice and locomotor activity in zebrafish larvae (Figure 3e).…”

“…[62] (d) AAP-βCD-based nanocontainers for nucleic acid delivery reported by Liu. [68] (e) Selective eDHFR inhibitor (21), [63] antagonistic inhibitor for vertebrate TRPA1 channel ( 22), [64] adrenergic neurotransmission modulator (23), [65] inhibitor of casein kinase 1δ (24). [66] Copyright permissions are obtained from respective publications.…”

Azoheteroarene und Diazocine als Molekulare Photoschalter: Selbstassemblierung, Responsive Materialien und Photopharmakologie

“…[62] (d) AAP-β-CD Nanokontainer für den Transport von Nukleinsäuren. [68] (e) Selektiver eDHFR Inhibitor ( 21), [63] Antagonist für einen vertebraten TRPA1 Kanal ( 22), [64] adrenergischer Neurotransmissionsmodulator ( 23), [65] Casein-Kinase 1δ Inhibitor (24). [66] Urheberrechtliche Genehmigungen wurden von den jeweiligen Verlagen erhalten.…”

“… [62] In einem kürzlich erschienenen Artikel verwendeten Mizukami und Mitarbeiter ein AAP‐Derivat als Inhibitor das selektiv an Escherichia coli ‐Dihydrofolatreduktase (eDHFR), jedoch nicht an menschliche DHFR (hDHFR) bindet (Abbildung 3e). [63] Die effizienten Photopharmakophor‐Analoga von Methotrexat (MTX, einem bekannten DHFR‐Inhibitor) ermöglichten eine kontrollierbare Inhibitoraktivität mit 50‐fach höherer Bindungsaffinität im Vergleich zum AB‐Analogon. AAP‐Derivate können auch als photoschaltbare Antagonisten für den TRPA1‐Kanal von Wirbeltieren fungieren, wie von der Gruppe von Peterson und Fuchter berichtet wurde (Abbildung 3e).…”