Azobenzene/Tetraethyl Ammonium Photochromic Potassium Channel Blockers: Scope and Limitations for Design of Para-Substituted Derivatives with Specific Absorption Band Maxima and Thermal Isomerization Rate

Abstract

Azobenzene/tetraethyl ammonium photochromic ligands (ATPLs) are photoactive compounds with a large variety of photopharmacological applications such as nociception control or vision restoration. Absorption band maximum and lifetime of the less stable isomer are important characteristics that determine the applicability of ATPLs. Substituents allow to adjust these characteristics in a range limited by the azobenzene/tetraethyl ammonium scaffold. The aim of the current study is to find the scope and limitations for the design of ATPLs with specific spectral and kinetic properties by introducing para substituents with different electronic effects. To perform this task we synthesized ATPLs with various electron acceptor and electron donor functional groups and studied their spectral and kinetic properties using flash photolysis and conventional spectroscopy techniques as well as quantum chemical modeling. As a result, we obtained diagrams that describe correlations between spectral and kinetic properties of ATPLs (absorption maxima of E and Z isomers of ATPLs, the thermal lifetime of their Z form) and both the electronic effect of substituents described by Hammett constants and structural parameters obtained from quantum chemical calculations. The provided results can be used for the design of ATPLs with properties that are optimal for photopharmacological applications.

Keywords: DENAQ; azobenzene; azobenzene thermal isomerization rate; photochromic ion channel blockers; photopharmacology; red-shifting azobenzenes; spectral tuning of azobenzene photoswitches.

Figure 1

The structure of azobenzene/tetraethyl ammonium photochromic ligands considered in the current study.

Figure 2

Dark-adapted and light-adapted spectra of investigated ATPLs in DMSO. Transient absorption UV-Vis spectra are shown in the insets. Spectral bands are related to E, Z isomers and ($$\pi ,{\pi }^{*}$$), ($$n,{\pi }^{*}$$) transitions. * For compounds 2 and 6 the band can be decomposed into two Gaussian functions (see Supplementary Materials for details).

Figure 3

Dark-adapted and light-adapted spectra of investigated ATPLs in water. Transient absorption UV-Vis spectra are shown in the insets. Spectral bands are related to E, Z isomers and ($$\pi ,{\pi }^{*}$$), ($$n,{\pi }^{*}$$) transitions. * For compounds 2 and 7 the band can be decomposed into two Gaussian functions (see Supplementary Materials for details).

Figure 4

The dependence of absorption band maximum of the E form ($${\lambda }_{max}^E$$) for the ($$\pi ,{\pi }^{*}$$) transitions on the Hammett constants of substituents ($$\sigma$$). Spectra are recorded in DMSO (1) and water (2). The dependencies were approximated by linear functions for $$\sigma$$ > 0 and $$\sigma$$ < 0 separately, parameters of approximations are given in the figure.

Figure 5

The dependence of absorption band maxima of the Z form ($${\lambda }_{max}^Z$$) for the ($$\pi ,{\pi }^{*}$$) and ($$n,{\pi }^{*}$$) transitions on the Hammett constants of substituents ($$\sigma$$). Spectra are recorded in DMSO (1,3) and water (2,4). The dependencies were approximated by linear functions for $$\sigma$$ > 0 and $$\sigma$$ < 0 separately, parameters of approximations are given in the figure.

Figure 6

The dependence of spectral shift between absorption band maxima of E and Z forms of ATPLs ($$\Delta {\lambda }_{max}={\lambda }_{max}^E$$ - $${\lambda }_{max}^Z$$) for the ($$\pi ,{\pi }^{*}$$) transitions on the Hammett constants of substituents ($$\sigma$$) in DMSO (1) and water (2).

Figure 7

The effect of the charge transfer on the absorption maximum of the considered ATPLs.

Figure 8

The dependence of $${\lambda }_{max}^Z$$ $$(\pi ,{\pi }^{*})$$ on the charge value relocated from/to a substituent after excitation in the considered ATPLs.

Figure 9

The dependence of the logarithm of thermal isomerization kinetic constant of Z ATPLs (ln(k)) on the Hammett constants of substituents ($$\sigma$$) in DMSO (1) and water (2). The values of thermal lifetimes of Z forms are also given in the figure. The dependencies were approximated by linear functions for $$\sigma$$ > 0 and $$\sigma$$ < 0 separately. Parameters of approximations are given in the figure.

Figure 10

The dependence of the logarithm of thermal isomerization kinetic constants of Z ATPLs (ln(k)) on the length of the double bond (in Å) of the azobenzene moiety in E ATPLs.

Figure 11

Dark-adapted and light-adapted spectra of compound 8 in DMSO (1) and water (2). Transient absorption UV-Vis spectrum in water is shown in the inset. Spectral bands are related to E, Z isomers and ($$\pi ,{\pi }^{*}$$), ($$n,{\pi }^{*}$$) transitions. * Thermal lifetime of E isomer in DMSO from the work [11].