Mechanistic Studies of the Photoinduced Quinone Trimethyl Lock Decaging Process

Abstract

Mechanistic studies of a general reaction that decages a wide range of substrates on exposure to visible light are described. The reaction involves a photochemically initiated reduction of a quinone mediated by an appended thioether. After reduction, a trimethyl lock system incorporated into the quinone leads to thermal decaging. The reaction could be viewed as an electron-transfer initiated reduction of the quinone or as a hydrogen abstraction -Norrish Type II -reaction. Product analysis, kinetic isotope effects, stereochemical labeling, radical clock, and transient absorption studies support the electron transfer mechanism. The differing reactivities of the singlet and triplet states are determined, and the ways in which this process deviates from typical quinone photochemistry are discussed. The mechanism suggests strategies for extending the reaction to longer wavelengths that would be of interest for applications in chemical biology and in a therapeutic setting.

Trimethyl Lock: A Multifunctional Molecular Tool for Drug Delivery, Cellular Imaging, and Stimuli‐Responsive Materials

“…[200] Compound 144 can be synthesized on as olid-phase support and consists of an octa-arginine cell-penetrating peptides equence that mediates cellular uptake, an uclear localization signal (NLS) that allows uptake into cell nuclei, and photosensitive amino acid 143 coupled to as erine bearingt wo peptide fragments of an uclear export signal (NES) as well as af luorescent moietyt hat allows localization of the compounds to be imaged. [202,203] The fact that quinone moieties can be photochemically reduced to their corresponding dihydroquinones is long known, [204][205][206][207] and severale xamples for which photoreduction is mediated by an adjacent sulfide [208,209] or amine [210][211][212][213][214][215][216][217] functionhave been reported. [200] Photochemicalc leavage of the compound by subsequent irradiation with UV light leads to the formation of a NES through an O-N-acyl shifti nr eleased N-terminal peptide 145,a si llustrated in Scheme 33.…”

“…Sulfide-and amine-substitutedb enzoquinoneTML esters and their reaction under irradiation with visible light. [203] Furthermore, strong kinetic isotope effects reveal that hydrogen abstraction is the crucial step for the overall process. [202] Comprehensivem echanistic studies on the conversion of sulfide-substituted TML benzoquinones of type As upport an ionic pathway for the photoreduction,a ss hown in Scheme36.…”

“…ChemBioChem 2018ChemBioChem , 19,1668ChemBioChem -1694 www.chembiochem.org 2018 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim monitored by NMR spectroscopy. [203] Furthermore,t wo possible applications of photosensitive TML moieties have been investigated. [203] Furthermore, strong kinetic isotope effects reveal that hydrogen abstraction is the crucial step for the overall process.…”

“…[200] Recently,D oughertya nd co-workers have presented ag eneral strategy for the direct photoinduced decay of quinonebased TML systems. [202,203] The fact that quinone moieties can be photochemically reduced to their corresponding dihydroquinones is long known, [204][205][206][207] and severale xamples for which photoreduction is mediated by an adjacent sulfide [208,209] or amine [210][211][212][213][214][215][216][217] functionhave been reported.…”

“…[202] Comprehensivem echanistic studies on the conversion of sulfide-substituted TML benzoquinones of type As upport an ionic pathway for the photoreduction,a ss hown in Scheme36. [203] Furthermore, strong kinetic isotope effects reveal that hydrogen abstraction is the crucial step for the overall process. [203] Furthermore,t wo possible applications of photosensitive TML moieties have been investigated.…”