A Structurally Simple Self-Immolative Reagent That Provides Three Distinct, Simultaneous Responses per Detection Event

Abstract

A general design is presented for a stimulus-responsive small molecule that is capable of responding to a specific applied chemical or physical signal by releasing two different types of pendant small molecules and a colorimetric indicator simultaneously. A key aspect of this design is the ease with which these reagents are prepared: typically, only four synthetic steps are required. Moreover, the modular construction strategy provides access to stimuli-responsive reagents that are capable of (i) responding to a variety of applied signals and (ii) releasing a number of different small molecules that contain primary alcohols, secondary alcohols, or phenols. These stimuli-responsive reagents are stable under physiological conditions (neither hydrolysis nor thermal degradation of the reagent occurs in significant quantity), and when they are exposed to the appropriate applied signal, they release both pendant small molecules and the colorimetric indicator completely within hours. Finally, unlike other functional groups, such as carbonates, that are used to connect alcohol-bearing molecules to controlled-release reagents, the linkage described in this article increases in hydrolytic stability (rather than decreases) as the pK(a) of the pendant alcohol decreases.

Synthetic Nano- and Micromachines in Analytical Chemistry: Sensing, Migration, Capture, Delivery, and Separation

“…Zhang et al (106) achieved higher sensitivity (micromolar) in such systems due to signal amplification: A specific analyte (β-D-glucuronidase, a biomarker of Escherichia coli ) triggered fluoride release from a small molecule, which in turn caused depolymerization and fluid pumping, as shown in Figure 3c. Continuing work in this area involves different amplification reactions that can provide linear or exponential responses with fast (burst release) (120) or slow (tunable) rates of amplification (121,122).…”

Stability, Kinetic, and Mechanistic Investigation of 1,8-Self-Immolative Cinnamyl Ether Spacers for Controlled Release of Phenols and Generation of Resonance and Inductively Stabilized Methides

“…The phenolic moiety is a key component for many biologically active drugs, fluorescent probes, and responsive materials . While strategies for protecting phenols in organic syntheses are vast, caging with a self-immolative spacer for prodrug therapy, diagnostics, and responsive materials is mostly limited to esters, carbonates, and benzyl ethers. , The ester and carbonate linkers have limited biological application because they only form moderately stable conjugates with higher p K a phenols or alcohols and can be subjected to nonspecific hydrolysis. , On the other hand, benzyl ethers form stable conjugates, and in a strictly aqueous (aq) environment, they have been successfully utilized in the activation of prodrugs . However, when this translates to a less polar solvent (e.g., 1:1 MeCN/buffer), a requirement for many responsive material applications, the benzyl ether is only capable of slow release of acidic phenols (p K a <9.2; t 1/2 < 3 h) .…”

A small molecule sensor for fluoride based on an autoinductive, colorimetric signal amplification reaction

“…Design of reagent 1. We designed reagent 1 with four considerations in mind: (i) the reagent must detect fluoride selectively (the tert-butyldimethylsilyl ether group provides this capability 16 ); (ii) a colorimetric readout must be generated for each reaction with fluoride to provide an unambiguous readout (generation of 4-aminobenzaldehyde provides this function 16,17 ); (iii) two molecules of fluoride must be released per reaction of 1 with fluoride, both to propagate the signal amplification reaction, and to accelerate the rate of the reaction (release of only one molecule of fluoride would propagate, but not accelerate the rate of the reaction); and (iv) the reagent that enables all of these capabilities must be accessible via an exceedingly short and inexpensive synthesis that makes the reagent an attractive starting point for use in resource-limited environments. 18 Synthesis of reagent 1.…”