Abstract
AbstractPhotoactivated drugs provide an opportunity to improve efficacy alongside reducing side‐effects in the treatment of severe diseases such as cancer. Described herein is a photoactivation decaging method of isobutylene‐caged thiols through a UV‐initiated thiol‐ene reaction. The method was demonstrated with an isobutylene‐caged cysteine, cyclic disulfide‐peptide, and thiol‐containing drug, all of which were rapidly and efficiently released under mild UV irradiation in the presence of thiol sources and a photoinitiator. Importantly, it is shown that the activity of histone deacetylase inhibitor largazole can be switched off when stapled, but selectively switched on within cancer cells when irradiated with non‐phototoxic light.
Highlights
[c] Dr G.J.L. Bernardes Instituto de Medicina Molecular Faculdade de Medicina, Universidade de Lisboa Avenida Professor Egas Moniz, 1649–028 Lisboa (Portugal) E-mail: gbernardes@medicina.ulisboa.pt
This covalently cross-linked network is able to undergo photomediated, reversible cleavage of its isobutylene backbone to allow chain rearrangement and relieve of structural strain. This method has been used to provide a reactive handle for reversible addition and exchange of biochemical moieties under cytocompatible conditions[12d]. Key to this reaction is the isobutylene structure capable of addition-fragmentation chain transfer (AFCT), in which the structure is attacked by the photoinitiated thiol radical in the presence of a photoinitiator (PI) to release the caged thiol part
General thiol-ene coupling reaction; b. the thiol-isobutylene decaging reaction. Inspired by this AFCT reaction, we hypothesized that the isobutylene structure could be used as a bridging graft to cage thiol-drugs and allow further controlled activation of anti-cancer drugs by means of a radical-mediated thiol-ene mechanism (Scheme 1)
Summary
[c] Dr G.J.L. Bernardes Instituto de Medicina Molecular Faculdade de Medicina, Universidade de Lisboa Avenida Professor Egas Moniz, 1649–028 Lisboa (Portugal) E-mail: gbernardes@medicina.ulisboa.pt Isobutylene-bridged polymer networks have been extensively studied to synthesize polymer networks through radical-initiated thiol-ene chemistry[12]. Inspired by this AFCT reaction, we hypothesized that the isobutylene structure could be used as a bridging graft to cage thiol-drugs and allow further controlled activation of anti-cancer drugs by means of a radical-mediated thiol-ene mechanism (Scheme 1).
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