http://pubs.acs.org/doi/pdf/10.1021/cr400546e

Fluorescent Sensors for Measuring Metal Ions in Living Systems

The dynamic chemical diversity of elements, ions and molecules that form the basis of life offers both a challenge and an opportunity for study. Small-molecule fluorescent probes can make use of selective, bioorthogonal chemistries to report on specific analytes in cells and in more complex biological specimens. These probes offer powerful reagents to interrogate the physiology and pathology of reactive chemical species in their native environments with minimal perturbation to living systems. This Review presents a survey of tools and tactics for using such probes to detect biologically important chemical analytes. We highlight design criteria for effective chemical tools for use in biological applications as well as gaps for future exploration.

Reaction-based small-molecule fluorescent probes for chemoselective bioimaging

Design strategies for water-soluble small molecular chromogenic and fluorogenic probes.

Small-molecule fluorescent probes embody an essential facet of chemical biology. Although numerous compounds are known, the ensemble of fluorescent probes is based on a modest collection of modular “core” dyes. The elaboration of these dyes with diverse chemical moieties is enabling the precise interrogation of biochemical and biological systems. The importance of fluorescence-based technologies in chemical biology elicits a necessity to understand the major classes of small-molecule fluorophores. Here, we examine the chemical and photophysical properties of oft-used fluorophores and highlight classic and contemporary examples in which utility has been built upon these scaffolds.

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Bright Ideas for Chemical Biology

A novel coumarin-based fluorogenic probe bearing the 2-picolyl unit (1) was developed as a fluorescent chemosensor with high selectivity and suitable affinity in biological systems toward Cu2+ over other cations tested. The fluorescence on−off mechanism was studied by femtosecond time-resolved fluorescence (TRF) upconversion technique and ab initio calculations. The receptor can be applied to the monitoring of Cu2+ ion in aqueous solution with a pH span 4−10. To confirm the suitability of 1 for biological applications, we also employed it for the fluorescence detection of the changes of intracellular Cu2+ in cultured cells. The results indicate that 1 should be useful for the fluorescence microscopic imaging and the study on the biological functions of Cu2+.

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Coumarin-Derived Cu2+-Selective Fluorescence Sensor: Synthesis, Mechanisms, and Applications in Living Cells

A chelation-enhanced fluorescence method for the detection of paramagnetic copper(II) ions is developed. Two dyes with unequal metal ion binding constants are used, each giving strong fluorescence enhancement in the presence of a diamagnetic reporter ion such as cadmium(II). Upon presentation of copper(II) to a 1:1:1 mixture of the two dyes and cadmium(II), the Cd(II) is displaced from one dye to the other, resulting in quenching of one dye by the Cu(II) and enhancement of the weaker binding dye by complexation of the Cd(II). Although several criteria must be met, this method holds promise for analysis of a wide range of analytes.

Ratiometric displacement approach to Cu(II) sensing by fluorescence.

Zinc plays an important role in biological processes. It is implicated in many diseases, including those affecting the brain. Imaging zinc is becoming crucial to the elucidation of zinc concentration, distribution, kinetics and functions in cells and tissues. This review highlights recent advances in the development of picolylamine-based tripodal compounds as zinc sensors, especially our work in the field of sensing “invisible” Zn(II) using steady-state fluorescence, fluorescence lifetimes and chiroptical spectroscopy. Our approach has emphasized creative ligand design and detection schemes. Utilizing tris(2-pyridylmethyl)amine-based N4 tripodal ligands has provided a flexible system for engineering zinc sensors with improved sensitivity, selectivity and contrast. Also included are results with tripodal ligands that have focused more on applications.

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Tailoring tripodal ligands for zinc sensing

Chiroptical switches have found application in the detection of a multitude of different analytes with a high level of sensitivity and in asymmetric catalysis to offer switchable stereoselectivity. A wide range of scaffolds have been employed that respond to metals, small molecules, anions and other analytes. Not only have chiroptical systems been used to detect the presence of analytes, but also other properties such as oxidation state and other physical phenomena that influence helicity and conformation of molecules and materials. Moreover, the tunable responses of many such chiroptical switches enable them to be used in the controlled production of either enantiomer or diastereomer at will in many important organic reactions from a single chiral catalyst through selective use of a low-cost inducer: Co-catalysts (guests), metal ions, counter ions or anions, redox agents or electrochemical potential, solvents, mechanical forces, temperature or electromagnetic radiation.

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Chiroptical switches: applications in sensing and catalysis

Protein tyrosine kinases serve as key mediators of signaling pathways, biochemical highways that control various aspects of cell behavior. Although fluorescent reporters of tyrosine kinases have been described, these species can suffer immediate phosphorylation upon exposure to the cellular milieu, thereby hindering a detailed analysis of kinase activity as a function of the cell cycle or exposure to environmental stimuli. The first example of a light-regulated tyrosine kinase reporter is described herein, which allows the investigator to control when kinase activity is sampled. In addition, the set of sensors created in this study contain different fluorophores, each with its own unique photophysical properties, thereby furnishing an array of choices that can be used in combination with other intracellular probes.

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Zhaohua Dai

Papers

Ratiometric displacement approach to Cu(II) sensing by fluorescence.

Tailoring tripodal ligands for zinc sensing

Chiroptical switches: applications in sensing and catalysis

Light-regulated sampling of protein tyrosine kinase activity.

Stereochemical control of Zn(II)/Cu(II) selectivity in piperidine tripod ligands.