A p‐Hydroxyphenacyl–Benzothiazole–Chlorambucil Conjugate as a Real‐Time‐Monitoring Drug‐Delivery System Assisted by Excited‐State Intramolecular Proton Transfer

Abstract

Among the well-known phototriggers,t he phydroxyphenacyl (pHP) group has consistently enabled the very fast, efficient, and high-conversion release of active molecules.D espite this unique behavior,t he pHP group has been ignored as ad elivery agent, particularly in the area of theranostics,b ecause of two major limitations:I ts excitation wavelength is below400 nm, and it is nonfluorescent. We have overcome these limitations by incorporating a2 -(2'-hydroxyphenyl)benzothiazole (HBT) appendage capable of rapid excited-state intramolecular proton transfer (ESIPT). The ESIPT effect also provided two unique advantages:Itassisted the deprotonation of the pHP group for faster release,a nd it was accompanied by adistinct fluorescence color change upon photorelease.I nvitro studies showed that the p-hydroxyphenacyl-benzothiazole-chlorambucil conjugate presents excellent properties,s uch as real-time monitoring,p hotoregulated drug delivery,and biocompatibility.

Visible-to-NIR-Light Activated Release: From Small Molecules to Nanomaterials

“…The nitrogen-containing substituents in 107 and 108 are positioned in a way that was expected to facilitate an excited-state intramolecular proton transfer (ESIPT) that would assist in the deprotonation of the p -hydroxyl group. Specifically, it was proposed that upon excitation to the singlet excited state, an ESIPT would occur, 631 followed by a transition to a triplet excited state, allowing the reaction to proceed as shown in Scheme 27 . 631 − 633 The hydrophobicity of the tetraphenylethylene 617 moiety in 108 enabled the formation of organic nanoparticles 633 using a reprecipitation technique.…”

“…Specifically, it was proposed that upon excitation to the singlet excited state, an ESIPT would occur, 631 followed by a transition to a triplet excited state, allowing the reaction to proceed as shown in Scheme 27 . 631 − 633 The hydrophobicity of the tetraphenylethylene 617 moiety in 108 enabled the formation of organic nanoparticles 633 using a reprecipitation technique. 564 Visible light-mediated photorelease (λ irr ≥ 410 nm) of a carboxylic acid 631 , 633 (chlorambucil) and a hydroxylamine 632 (an NO-donating NONOate; 634 see section 4.2 ) from 107 and 108 proceeded in high chemical yields, with the corresponding p -hydroxyphenylacetic acid derivative being the sole additional photoproduct 631 , 633 ( Scheme 28 ).…”

“…Uncaging was accompanied by a 70–100 nm blue-shift of the fluorescence emission spectrum, enabling real-time quantitative monitoring of the reaction’s progress in live cultured cells. 631 − 633 …”

Light-controlled twister ribozyme with single-molecule detection resolves RNA function in time and space

“…Photocaged 1 presents a distinct hydrogen bonding pattern from guanosine and is an attractive tool for studying dynamics due to the rapid release of the native nucleotide following photolysis. Longer wavelength absorptivity (≥400 nm) was required to adapt this tool for single-molecule TIRF microscopy experiments, and a recent report indicated that the benzothiazole group would fulfill this requirement (23). The viability of 1 as a photocaged precursor for guanosine was established by photolyzing the nucleoside in aqueous methanol (1:1) using light-emitting diodes (395-405 nm).…”

Monitoring of uncaging processes by designing photolytical reactions

“…The group of Pradeep Singh was able to overcome these limitations by adding a 2-(2'-hydroxyphenyl) benzothiazole (HBT) core to the pHP. 39 This HBT core induces a rapid ESIPT phenomenon which can assist the deprotonation of the pHP group for a faster release, with excitation higher than 400 nm as well as a distinct fluorescence shift upon photorelease. Using this pro-fluorescent PPG, the authors were able to develop a drug release system leading to the liberation of Chlorambucil (Cbl) using light with real time monitoring of the uncaging process.…”