Sign Inversion in Photopharmacology: Incorporation of Cyclic Azobenzenes in Photoswitchable Potassium Channel Blockers and Openers

Abstract

Photopharmacology relies on ligands that change their pharmacodynamics upon photoisomerization. Many of these ligands are azobenzenes that are thermodynamically more stable in their elongated trans‐configuration. Often, they are biologically active in this form and lose activity upon irradiation and photoisomerization to their cis‐isomer. Recently, cyclic azobenzenes, so‐called diazocines, have emerged, which are thermodynamically more stable in their bent cis‐form. Incorporation of these switches into a variety of photopharmaceuticals could convert dark‐active ligands into dark‐inactive ligands, which is preferred in most biological applications. This “pharmacological sign‐inversion” is demonstrated for a photochromic blocker of voltage‐gated potassium channels, termed CAL, and a photochromic opener of G protein‐coupled inwardly rectifying potassium (GIRK) channels, termed CLOGO.

Photoswitchable Azo- and Diazocine-Functionalized Derivatives of the VEGFR-2 Inhibitor Axitinib

“…Up to now, there are only a few but successful examples of photoswitchable drugs containing diazocines as the switching unit. Diazocines were used to photoswitch peptide conformations [ 25 ], DNA hybridization [ 26 ], and potassium channel activities [ 27 , 28 ]. Based on these examples, we designed and synthesized diazocine-functionalized derivatives of axitinib.…”

In Situ Observation of Photoswitching by NMR Spectroscopy: A Photochemical Analogue to the Exchange Spectroscopy Experiment

“…Compound 3 was developed to achieve the reverted stability of ( E )- and ( Z )-isomers. Especially in the field of photopharmacology, a stable and inactive state is highly desirable . Bridging the two aromatic rings moves the n−π* bands utilized in the switching process further to the red part of the spectrum .…”

Metal Ion Mediated Instant Z → E Isomerization of Azobenzene Macrocycles in the Absence of Light

“…The half-lives for the thermal Z → E reversal could last up to weeks depending on the substituent on the phenyl rings. 16 Electrochemical reduction of azobenzene in the Z-form can lead to rapid Z → E isomerization. 17, 18 Enhanced Z → E isomerization upon the addition of cyclodextrin-coated gold nanoparticles has been reported.…”