Shawn C. Burdette

Meeting of the minds: Metalloneurochemistry

Metalloneurochemistry is the study of metal ion function in the brain and nervous system at the molecular level. Research in this area is exemplified through discussion of several forefront areas where significant progress has been made in recent years. The structure and function of ion channels have been elucidated through high-resolution x-ray structural work on the bacterial K+ ion channel. Selection of potassium over sodium ions is achieved by taking advantage of key principles of coordination chemistry. The role of calcium ions in neuronal signal transduction is effected by several Ca2+-binding protein such as calmodulin, calcineurin, and synaptotagmin. Structural changes in response to calcium ion concentrations allow these proteins to function in memory formation and other neurochemical roles. Metallochaperones help to achieve metal ion homeostasis and thus prevent neurological diseases because of metal ion imbalance. Much detailed chemical information about these systems has become available recently. Zinc is another important metal ion in neuroscience. Its concentration in brain is in part controlled by metallothionein, and zinc is released in the hippocampus at glutamatergic synapses. New fluorescent sensors have become available to help track such zinc release.

ICCC34 — golden edition of coordination chemistry reviews. Coordination chemistry for the neurosciences

Abstract Metal ions are integral components of numerous enzymes and proteins. Although the field of bioinorganic chemistry has not focused on the brain and central nervous system, metal ions are vital to many neurological functions and are implicated in several neurological disorders. In this review, we give a brief overview of the functions of metal ions in neurobiology and the highlight recent advances and uses of fluorescent sensors to study the neurotransmitters nitric oxide and zinc. Emphasis is placed on work from our laboratory to devise sensors for NO and Zn 2+ , a project that was initiated 3 years ago in a continuing effort to study the inorganic chemistry of the nervous system.

FerriCast: A Macrocyclic Photocage for Fe3+

The non-siderophoric Fe(3+) photocage FerriCast (4,5-dimethoxy-2-nitrophenyl)-[4-(1-oxa-4,10-dithia-7-aza-cyclododec-7-yl)phenyl] methanol (2) has been prepared in high yield using an optimized two-step reaction sequence that utilizes a trimethylsilyl trifluoromethanesulfonate (TMSOTf) assisted electrophilic aromatic substitution as the key synthetic step. Spectrophotometric assessment of Fe(3+) binding to FerriCast revealed a binding stoichiometry and metal ion affinity dependent on the nature of the counterion. Exposure of FerriCast to 350 nm light initiates a photoreaction that converts FerriCast into FerriUnc (4,5-dimethoxy-2-nitrosophenyl)-[4-(1-oxa-4,10-dithia-7-aza-cyclododec-7-yl)phenyl]-methanone), which binds Fe(3+) less strongly owing to resonance delocalization of the anilino lone pair into the benzophenone pi-system. The release of Fe(3+) upon photolysis of FerriCast also was evaluated using a previously reported turn-on fluorescent sensor that utilizes the same macrocyclic ligand (4-(1-oxa-4,10-dithia-7-aza-cyclododec-7-yl)phenyl, AT(2)12C4). In contrast to the original reports on AT(2)12C4-based Fe(3+) sensors, FerriCast does not interact with ferric iron in aqueous solution. Introduction of oxygen containing solvents (MeOH, H(2)O, DMSO, MES, and phosphate buffers) to CH(3)CN solutions of metalated FerriCast lead to rapid decomplexation as measured by UV-visible spectroscopy. Further investigations contradicted the published conclusions on the aqueous coordination chemistry of AT(2)12C4, but also confirmed the unique and unexpected selectivity of the macrocycle for Fe(3+) in nonaqueous solvents. The crystallographic analysis of [Cu(AT(2)12C4)Cl](+) provides a rare example of a bifurcated hydrogen bond, and evidence for redox chemistry with the ligand. Spectrophotometric analysis of the model ligand with redox active metal ions provide evidence for AT(2)12C4(*+), a quasi-stable species the presence of which suggests caution should be taken when evaluating the interaction of aniline-containing systems with redox active metal ions.

Photoinduced Release of Zn2+ with ZinCleav-1: a Nitrobenzyl-Based Caged Complex

Caged complexes are metal ion chelators that release analytes when exposed to light of a specific wavelength. The synthesis and properties of ZinCleav-1, a cage for Zn(2+) that fragments upon photolysis, is reported. The general uncaging strategy involves integrating a nitrobenzyl group on the backbone of the ligand so that a carbon-heteroatom bond is cleaved by the photoreaction. The caged complex was obtained using a new synthetic strategy involving a Strecker synthesis to prepare a key aldehyde intermediate. ZinCleav-1 has a K(d) of 0.23 pM for Zn(2+) as measured by competitive titration with [Zn(PAR)(2)] (PAR = 4-(2-pyridyl-2-azo) resorcinol). The quantum yield for ZinCleav-1 is 2.4% and 0.55% for the apo and Zn(2+) complex, respectively. The ability of ZinCleav-1 to increase free [Zn(2+)] is calculated theoretically using the binding constants for the uncaged photoproducts, and demonstrated practically by using a fluorescent sensor to image the liberated Zn(2+). Free Zn(2+) may function as a neurotransmitter and have a role in the pathology of several neurological diseases. Studying these physiological functions remains challenging because Zn(2+) is silent to most common spectroscopic techniques. We expect ZinCleav-1 to be the first in a class of caged complexes that will facilitate biological investigations.

Photochemical Tools for Studying Metal Ion Signaling and Homeostasis

Metal ions have well-established catalytic and structural roles in proteins. Much of the knowledge acquired about metalloenzymes has been derived using spectroscopic techniques and X-ray crystallography, but these methodologies are less effective for studying metal ions that are not tightly bound to biomacromolecules. In order to prevent deleterious chemistry, cells tightly regulate the uptake, distribution, and intracellular concentrations of metal ions. Investigation into these homeostasis mechanisms has necessitated the development of alternative ways to study metal ions. Photochemical tools such as small molecule and protein-based fluorescent sensors as well as photocaged complexes have provided insight into the homeostasis and signaling mechanisms of Ca(2+), Zn(2+), and Cu(+), but a comprehensive picture of metal ions in biology will require additional development of these techniques, which are reviewed in this Current Topics article.

FerriNaphth: a fluorescent chemodosimeter for redox active metal ions.

FerriNaphth, a fluorescent chemodosimeter for Fe(III), has been prepared and characterized. The probe consists of a catechol ligand linked to a naphthalimide fluorophore by an aniline nitrogen linker. Upon exposure to Fe(III), the aminocatechol of FerriNaphth is oxidized to the corresponding quinone, which in its imine-one tautomer, is hydrolyzed to liberate a fluorescent aminonaphthalimide derivative. The fluorescence behavior is consistent with oxidation being promoted by metal coordination.

Isoquinoline-derivatized tris(2-pyridylmethyl)amines as fluorescent zinc sensors with strict Zn2+/Cd2+ selectivity

Tris(2-pyridylmethyl)amine-based fluorescent ligands, N,N-bis(1-isoquinolylmethyl)-2-pyridylmethylamine (1-isoBQPA) and N,N-bis(7-methoxy-1-isoquinolylmethyl)-2-pyridylmethylamine (7-MeO-1-isoBQPA), have been prepared and the Zn(2+)-induced fluorescence enhancement has been investigated. Upon excitation at 324 nm, 1-isoBQPA exhibits a very weak emission (ϕ = ~0.010) in DMF-H2O (1 : 1). Upon Zn(2+) addition, the 1-isoBQPA fluorescence increases (ϕ(Zn) = 0.055) at 357 nm and 464 nm. The fluorescence enhancement at longer wavelengths is Zn(2+)-specific, whereas Cd(2+) induces a small emission increase at 464 nm (I(Cd)/I0 = 1.1, I(Cd)/I(Zn) = 14%). The Zn(2+)/Cd(2+) selectivity of the fluorescent response correlates with the Cd-N(isoquinoline) and Zn-N(isoquinoline) bond distances measured in the crystal structures. Introduction of methoxy groups into the 1-isoBQPA chromophore enhances the fluorescence significantly (ϕ(Zn) = 0.213), which affords 7-MeO-1-isoBQPA properties amenable for fluorescence microscopy in living cells.

Molecular switches: Hydrazones double down on zinc

Molecular engineers have long relied on a single light-driven event or chemical input to induce structural changes in switching systems. By carefully designing two hydrazone-based switches, it has now been shown that a single metal-binding event can trigger a signalling cascade that results in the isomerization of two different molecules.

Probing Nitrobenzhydrol Uncaging Mechanisms Using FerriCast

The FerriCast derivative FC-NDBF was synthesized from 3-methyl-2-nitrodibenzofuran (NDBF). The photochemistry of the target Fe(3+) photocage and several related congeners provides mechanistic insight into the uncaging quantum yields of nitrobenzhydrol-derived ligands.

Methods for Preparing Metal Ion Photocages: Application to the Synthesis of CrownCast

Three different synthetic strategies were utilized in the construction of a novel class of macrocyclic containing o-nitrobenzhydrol group II cation cages. The synthetic methodology presented herein is unparalleled in scope toward the preparation of caged complexes for various main group and transition block cations.