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Contrasting Photo-Switching Rates in Azobenzene Derivatives: How the Nature of the Substituent Plays a Role.

ABSTRACT: A molecular design approach was used to create asymmetrical visible light-triggered azo-derivatives that can be good candidates for polymer functionalization. The specific electron-donor substituted molecules were characterized and studied by means of NMR analyses and UV-visible spectroscopy, comparing the results with Time Dependent Density Functional (TD-DFT) calculations. A slow rate of isomerization (ki = 1.5 × 10-4 s-1) was discovered for 4-((2-hydroxy-5methylphenyl) diazenyl)-3-methoxybenzoic acid (AZO1). By methylating this moiety, it was possible to unlock the isomerization mechanism for the second molecule, methyl 3-methoxy-4-((2-methoxy-5-methylphenyl) diazenyl)benzoate (AZO2), reaching promising isomerization rates with visible light irradiation in different solvents. It was discovered that this rate was heightened by one order of magnitude (ki = 3.1 × 10-3 s-1) for AZO2. A computational analysis using density functional (DFT/PBE0) and wavefunction (QD-NEVPT2) methodologies provided insight into the photodynamics of these systems. Both molecules require excitation to the second (S2) excited state situated in the visible region to initiate the isomerization. Two classic mechanisms were considered, namely rotation and inversion, with the former being energetically more favorable. These azo-derivatives show potential that paves the way for future applications as building blocks of functional polymers. Likewise, they could be really effective for the modification of existing commercial polymers, thus transferring their stimuli responsive properties to polymeric bulky structures, converting them into smart materials.

SUBMITTER: Pirone D

PROVIDER: S-EPMC7284787 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND AND PURPOSE:The photo-isomerizable local anaesthetic, quaternary ammonium-azobenzene-quaternary ammonium (QAQ), provides rapid, optical control over pain signalling without involving genetic modification. In darkness or in green light, trans-QAQ blocks voltage-gated K+ and Na+ channels and silences action potentials in pain-sensing neurons. Upon photo-isomerization to cis with near UV light, QAQ blockade is rapidly relieved, restoring neuronal activity. However, the molecular mechanism of cis and trans QAQ blockade is not known. Moreover, the absorption spectrum of QAQ requires UV light for photo-control, precluding use deep inside neural tissue. EXPERIMENTAL APPROACH:Electrophysiology and molecular modelling were used to characterize the binding of cis and trans QAQ to voltage-gated K+ channels and to develop quaternary ammonium-ethylamine-azobenzene-quaternary ammonium (QENAQ), a red-shifted QAQ derivative controlled with visible light. KEY RESULTS:trans QAQ was sixfold more potent than cis QAQ, in blocking current through Shaker K+ channels. Both isomers were use-dependent, open channel blockers, binding from the cytoplasmic side, but only trans QAQ block was slightly voltage dependent. QENAQ also blocked native K+ and Na+ channels preferentially in the trans state. QENAQ was photo-isomerized to cis with blue light and spontaneously reverted to trans within seconds in darkness, enabling rapid photo-control of action potentials in sensory neurons. CONCLUSIONS AND IMPLICATIONS:Light-switchable local anaesthetics provide a means to non-invasively photo-control pain signalling with high selectivity and fast kinetics. Understanding the mode of action of QAQ and related compounds will help to design of drugs with improved photo-pharmacological properties. LINKED ARTICLES:This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc.

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Contrasting Photo-Switching Rates in Azobenzene Derivatives: How the Nature of the Substituent Plays a Role.

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