A FRET probe for the detection of alkylating agents

Abstract

A fluorogenic FRET probe allows efficient detection of toxic alkylating agents through a self-immolative reaction.

Recent advances in self-immolative linkers and their applications in polymeric reporting systems

“…Over the past two decades, the chemistry of self-immolative systems has received significant attention and the technology has developed sufficiently to permit application in areas as diverse as the pharmaceutical sector, [1][2][3] degrade-on-demand adhesives, 4-6 chemosensors 7 and the detection or disclosure of toxic compounds. [8][9][10] In 1981 seminal studies conducted by Katzenellenbogen and co-workers on prodrugs led to the term 'self-immolative connector' being proposed, and this degradable unit has subsequently been referred to in the literature as a 'self-immolative spacer' or 'self-immolative linker'. 11 The chemistry of self-immolative systems has been the subject of several reviews in the past decade, and indeed we published a review a decade ago on the topic of self-immolative linkers in polymeric delivery systems.…”

Self-Immolative System for Disclosure of Reactive Electrophilic Alkylating Agents: Understanding the Role of the Reporter Group

“…Crystals of 22, 23, 24, 25, 26, 27, and 28 were mounted under paratone-N oil and flash-cooled to either 100 K (22,23,26,27,28) or 150 K (24,25) under nitrogen in an Oxford Cryosystems Cryostream. Single-crystal X-ray intensity data were collected using either an Agilent Gemini S Ultra diffractometer (Mo Kα radiation (λ = 0.71073 Å)) (24,25) or a Rigaku XtaLAB Synergy diffractometer (Cu Kα radiation (λ = 1.54184 Å)) (22,23,26,27,28). The data were reduced within CrysAlisPro software.…”

“…Recently, a related approach for detection of alkylating agents has been reported using a Förster resonance energy-transfer (FRET)-based profluorescent probe. 24 In this system, alkylation of the probe results in the formation of a quaternary ammonium salt, which increases its leaving group capacity allowing the probe to facilitate the 1,6-elimination of the self-immolative process. When the elimination proceeds, the fluorophore is no longer quenched and can emit a fluorescence signal.…”

“…Stimuli-responsive compounds, − such as self-immolative molecules and polymers, − have become significant targets in organic-based material development as systems of this type offer enormous potential in a diverse range of applications that span drug delivery, − biological and chemical sensors, , diagnostics, and degradable polymers or degrade-on-demand adhesives. − The seminal report by Katzenellenbogen and co-workers, based upon the “prodrug” concept discussed by Albert, set in place the key molecular design for self-immolative materials that have been explored and refined by several groups in recent years, one in which a substrate-specific trigger is coupled via a degradable linker group to a reporter moiety. Activation or deprotection of the trigger moiety, by either nucleophiles or electrophiles, − renders the immolative linker unit labile via generation of an electron-rich center that then initiates a cascade of electrons and culminates in the release of the reporter group from the linker group. When designing a self-immolative system for a specific application, the delicate balance of reactivity and stability of each of the key components ( i.e ., trigger, linker, reporter) must be assessed and optimized.…”

“…A diphenylphosphine nucleophile was used as it offered the best balance between reactivity toward electrophiles while also offering reasonable stability toward aerobic oxidation. Recently, a related approach for detection of alkylating agents has been reported using a Förster resonance energy-transfer (FRET)-based profluorescent probe . In this system, alkylation of the probe results in the formation of a quaternary ammonium salt, which increases its leaving group capacity allowing the probe to facilitate the 1,6-elimination of the self-immolative process.…”