Indicator displacement assays (IDAs): the past, present and future.

Indicator displacement assays (IDAs) offer a unique and innovative approach to molecular sensing. IDAs can facilitate the detection of a range of biologically/environmentally important species, provide a method for the detection of complex analytes or for the determination and discrimination of unknown sample mixtures. These attributes often cannot be achieved by traditional molecular sensors i.e. reaction-based sensors/chemosensors. The IDA pioneers Inouye, Shinkai, and Anslyn inspired researchers worldwide to develop various extensions of this idea. Since their early work, the field of indicator displacement assays has expanded to include: enantioselective indicator displacement assays (eIDAs), fluorescent indicator displacement assays (FIDAs), reaction-based indicator displacement assays (RIAs), DimerDye disassembly assays (DDAs), intramolecular indicator displacement assays (IIDAs), allosteric indicator displacement assay (AIDAs), mechanically controlled indicator displacement assays (MC-IDAs), and quencher displacement assays (QDAs). The simplicity of these IDAs, coupled with low cost, high sensitivity, and ability to carry out high-throughput automation analysis (i.e., sensing arrays) has led to their ubiquitous use in molecular sensing, alongside the other common approaches such as reaction-based sensors and chemosensors. In this review, we highlight the various design strategies that have been used to develop an IDA, including the design strategies for the newly reported extensions to these systems. To achieve this, we have divided this review into sections based on the target analyte, the importance of each analyte and then the reported IDA system is discussed. In addition, each section includes details on the benefit of the IDAs and perceived limitations for each system. We conclude this Tutorial Review by highlighting the current challenges associated with the development of new IDAs and suggest potential future avenues of research.

Deferasirox (ExJade): An FDA-Approved AIEgen Platform with Unique Photophysical Properties.

Deferasirox, ExJade, is an FDA-approved iron chelator used for the treatment of iron overload. In this work, we report several fluorescent deferasirox derivatives that display unique photophysical properties, i.e., aggregation-induced emission (AIE), excited state intramolecular proton transfer, charge transfer, and through-bond and through-space conjugation characteristics in aqueous media. Functionalization of the phenol units on the deferasirox scaffold afforded the fluorescent responsive pro-chelator ExPhos, which enabled the detection of the disease-based biomarker alkaline phosphatase (ALP). The diagnostic potential of these deferasirox derivatives was supported by bacterial biofilm studies.

Metal-based imaging agents: progress towards interrogating neurodegenerative disease.

Central nervous system (CNS) neurodegeneration is defined by a complex series of pathological processes that ultimately lead to death. The precise etiology of these disorders remains unknown. Recent efforts show that a mechanistic understanding of the malfunctions underpinning disease progression will prove requisite in developing new treatments and cures. Transition metals and lanthanide ions display unique characteristics (i.e., magnetism, radioactivity, and luminescence), often with biological relevance, allowing for direct application in CNS focused imaging modalities. These techniques include positron emission tomography (PET), single-photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), and luminescent-based imaging (LumI). In this Tutorial Review, we have aimed to highlight the various metal-based imaging techniques developed in the effort to understand the pathophysiological processes associated with neurodegeneration. Each section has been divided so as to include an introduction to the particular imaging technique in question. This is then followed by a summary of key demonstrations that have enabled visualization of a specific neuropathological biomarker. These strategies have either exploited the high binding affinity of a receptor for its corresponding biomarker or a specific molecular transformation caused by a target species, all of which produce a concomitant change in diagnostic signal. Advantages and disadvantages of each method with perspectives on the utility of molecular imaging agents for understanding the complexities of neurodegenerative disease are discussed.

Transition metal chelators, pro-chelators, and ionophores as small molecule cancer chemotherapeutic agents.

Cancer is among the leading causes of death worldwide. Although a number of new treatment options have been developed in recent years, there remains a need for improved chemotherapies. The primary challenges facing new cancer drugs include: (1) improving patient quality of life, (2) overcoming drug resistance and (3) lowering reoccurrence rates. Major drawbacks of current chemotherapeutics arise from poor selectivity towards cancer cells, dose limiting toxicities, compliance-reducing side effects, and an inability to address resistance mechanisms. Chemotherapeutics that fail to achieve complete eradication of the disease can also lead to relapse and promote treatment resistance. New strategies to overcome these drawbacks include the use of transition metal chelators and ionophores to alter selectively the concentrations of iron, copper, and zinc in cancer cells. A number of metal chelators have successfully demonstrated cytotoxicity and targeted activity against drug-resistant cancer cells; several have proved effective against cancer stem cells, a significant cause of tumour reoccurrence. However, problems with formulation and targeting have been noted. Recent efforts have thus focused on the design of pro-chelators, inactive versions of chelators that are designed to be activated in the tumour. This is an appealing strategy that may potentially increase efficacy towards cancer-resistant malignant cells. This Tutorial Review summarizes recent progress involving transition metal chelators, pro-chelators, and ionophores as potential cancer chemotherapeutics. We will focus on the reported agents that are able to coordinate iron, copper, and zinc.

Magnetic-Field-Induced Modulation of Charge-Recombination Dynamics in a Rosarin-Fullerene Complex.

Charge-recombination processes are critical for photovoltaic applications and should be suppressed for efficient charge transport. Here, we report that an applied magnetic field (0-1 T) can be used control the charge-recombination dynamics in an expanded rosarin-C60 complex. In the low magnetic field regime (<100 mT), the charge-recombination rate slows down due to hyperfine coupling, as inferred from transient absorption spectroscopic analyses. In contrast, in the high field regime, i.e., over 500 mT, the charge-recombination rate recovers and increases because the Δg mechanism facilitates spin conversion to a triplet charge-separated state (S to T0 ) that undergoes rapid charge-recombination to a localized rosarin triplet state. Therefore, we highlight the charge-recombination rate and the localized triplet state population can be modulated by the magnetic field in charge donor/acceptor non-covalent complexes.

Porphyrinoid f-Element Complexes.

Porphyrin and related pyrrole-containing macrocycles, collectively porphyrinoids, are versatile ligands that allow access to a multitude of coordination modes. Judicious modification of the porphyrin core as well as the pendant substituents has extended the coordination chemistry of porphyrinoids to include systems that are able to stabilize f-block element complexes with possible utility. This review focuses on our group's efforts to prepare expanded porphyrin and porphyrinogen ligands that can serve as tools to study and apply f-element metal coordination chemistry: it covers the background of the topic, selected syntheses, and application of these species in the chemical and medical sciences.

Condition-Dependent Coordination and Peroxidase Activity of Hemin-Aß Complexes.

The peroxidase activity of hemin-peptide complexes remains a potential factor in oxidative damage relevant to neurodegeneration. Here, we present the effect of temperature, ionic strength, and pH relevant to pathophysiological conditions on the dynamic equilibrium between high-spin and low-spin hemin-Aß40 constructs. This influence on peroxidase activity was also demonstrated using 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and dopamine (DA) oxidation rate analyses with increasing ratios of Aß16 and Aß40 (up to 100 equivalents). Interaction and reactivity studies of aggregated Aß40-hemin revealed enhanced peroxidase activity versus hemin alone. Comparison of the results obtained using Aß16 and Aß40 amyloid beta peptides revealed marked differences and provide insight into the potential effects of hemin-Aß on neurological disease progression.

Synthesis and Characterization of a Binuclear Copper(II)-dipyriamethyrin Complex: [Cu2(dipyriamethyrin)(µ2-1,1-acetato)2].

The reaction between dipyriamethyrin and copper(II) acetate [Cu(OAc)2] afforded what is, to our knowledge, the first transition metal-dipyriamethyrin complex. Molecular and electronic characterization of this binuclear Cu(II) complex via EPR, UV-vis, and single crystal X-ray diffraction analysis revealed marked differences between the present constructs and previously reported binuclear copper(II) hexaphyrin species. UV-vis titration analyses provided evidence for a homotropic positive allosteric effect, wherein the binuclear species is formed without significant intermediacy of a monomeric complex.

Cation-based Structural Tuning of Pyridine Dipyrrolate Cages and Morphological Control over Their Self-assembly.

Different pyridine dipyrrolate cages including cage-based dimers and polymers may be fabricated in a controlled manner from the same two starting materials, namely, an angular ligand 1 and Zn(acac)2, by changing the counter cation source. With tetrabutylammonium (TBA+) and dimethyl viologen (DMV2+), Cage-3 and Cage-5 are produced. In these cages, two ligands act as bridges and serve to connect together two cage subunits to produce higher order ensembles. In Cage-3 and Cage-5, the TBA+ and DMV2+ counter cations lie outside the cavities of the respective cages. This stands in contrast to what is seen with a previously reported system, Cage-1, wherein dimethylammonium (DMA+) counter cations reside within the cage cavity. When the counter cations are tetraethylammonium (TEA+) and bis(cyclopentadienyl) cobalt(III) (Cp2Co+), polymeric cage materials, PC-1 and PC-2, are formed, respectively. The counter cations thus serve not only to balance charge but also to tune the structural features as a whole. The organic cations used in the present study also act to modulate the further assembly of individual cages. The present cation-based tuning emerges as a new method for a fine-tuning of the multidimensional morphology of self-assembled inorganic materials.

In-Plane Thorium(IV), Uranium(IV), and Neptunium(IV) Expanded Porphyrin Complexes.

Here we report the first series of in-plane thorium(IV), uranium(IV), and neptunium(IV) expanded porphyrin complexes. These actinide (An) complexes were synthesized using a hexa-aza porphyrin analogue, termed dipyriamethyrin, and the nonaqueous An(IV) precursors, ThCl4(DME)2, UCl4, and NpCl4(DME)2. The molecular and electronic structures of the ligand, each An(IV) complex, and a corresponding uranyl(VI) complex were characterized using nuclear magnetic resonance (NMR) and UV-vis spectroscopies as well as single-crystal X-ray diffraction analysis. Computational analyses of these complexes, coupled to their structural features, provide support for the conclusion that a greater degree of covalency in the ligand-cation orbital interactions arises as the early actinide series is traversed from Th(IV) to U(IV) and Np(IV). The axial ligands in the present An(IV) complexes proved labile, allowing for the electronic features of these complexes to be further modified.

Gram-Scale Synthesis of a Bench-Stable 5,5″-Unsubstituted Terpyrrole.

The controlled preparation of higher order oligopyrrolic species holds broad utility across the chemical and material sciences. Here, we describe the gram-scale synthesis of a bench-stable 5,5″-unsubstituted terpyrrole in excellent yield via a tandem Suzuki cross-coupling with in situ deprotection. The solution and solid-state stability as well as UV-vis, fluorescence, and single crystal X-ray diffraction structure are also detailed.

Lanthanide Texaphyrins as Photocatalysts.

Here, we report the use of gadolinium(III)-, lutetium(III)-, and lanthanum(III)-texaphyrins as bioinspired photocatalysts that promote a novel approach to the degradation of curcumin, a 1,3-diketo-containing natural product. Complexation of curcumin to the lanthanide centers of the texaphyrins yields stable species that display limited reactivity in the dark or under anaerobic conditions. However, upon exposure to mWatt intensity light (pocket flashlight) or simply under standard laboratory illumination in the presence of atmospheric oxygen, substrate oxidation occurs readily to generate curcumin-derived cleavage products. These latter species were identified on the basis of spectroscopic and mass spectrometric analyses. The mild nature of the activation conditions serves to highlight a potential new role for photoactive lanthanide complexes.

An Expanded Porphycene with High NIR Absorptivity That Stabilizes Two Different Kinds of Metal Complexes.

A new expanded porphycene with 26 π-electrons has been prepared by the McMurry coupling of 1,4-bis(3,4-diethyl-2-pyrryl)benzene dialdehyde. Expansion of the porphycene framework provides a ligand capable of stabilizing a bis(rhodium) and a monoruthenium complex. These new porphycene derivatives absorb strongly in the NIR spectral region, with appreciable absorptivity up to 1300 nm. On the basis of their ground- and excited-state spectroscopic features and structural parameters, both the free-base system and the bis(rhodium) complex are considered to be Hückel-type aromatic systems. This conclusion is supported by DFT calculations.

Expanded Rosarin: A Versatile Fullerene (C60) Receptor.

An expanded rosarian (P3P6) with a bowl-like conformation has been prepared and characterized in a one-pot procedure that involves condensing a bispyrrole pyridine precursor (P1P2) with benzaldehyde, followed by oxidation. Single crystal X-ray diffraction analysis reveals a bowl-like conformation in the solid state with an upper rim diameter defined by the meso-phenyl substituents of ca. 13.5 Å and a depth of roughly 6.3 Å. P3P6 forms both 1:1 and 2:1 complexes with C60 in the solid state. DFT reveals similar energies for the two binding modes. A 1:1 binding stoichiometry dominates in 1,2-dichlorobenzene-d4 at the millimolar concentrations dictated by solubility consideration. The solution phase interactions between rosarian and C60 were studied using 1H NMR, UV-vis, and femtosecond transient absorption spectroscopies in 1,2-dichlorobenzene-d4 or toluene. To our knowledge, this is the first report of an unfunctionalized porphyrinoid that forms a well-defined complex with C60 in solution as well as in solid state.

Naphthylbipyrrole-Containing Amethyrin Analogue: A New Ligand for the Uranyl (UO22+) Cation.

Using naphthobipyrrole as a functional building block, a new expanded porphyrin, naphthoisoamethyrin, was prepared in 85% yield under acid-catalyzed [4 + 2] MacDonald coupling conditions. Treatment of naphthoisoamethyrin with the nonaqueous uranyl silylamide salt [UO2[N(SiMe3)2]2·2THF] yielded the corresponding uranyl complex. Upon metalation, naphthoisoamethyrin undergoes a two-electron oxidation to yield a formal 22 π-electron aromatic species, as inferred from 1H NMR and UV-vis spectroscopy, as well as cyclic voltammetry.

Synthesis and Characterization of a Binuclear Copper(II) Naphthoisoamethyrin Complex Displaying Weak Antiferromagnetic Coupling.

The reaction between a naphthylbipyrrole-containing hexaphyrin-type expanded porphyrin and copper acetate affords a bench-stable dicopper(II) complex. UV-vis spectroscopy, cyclic voltammetry, and X-ray crystallographic analysis measurements provide support for the conclusion that this complex displays aromatic features. A weak antiferromagnetic exchange interaction between the binuclear copper(II) ions is evidenced by variable-temperature electron paramagnetic resonance and by fitting of the bulk magnetic susceptibility to a dimer model, yielding J = -5.1 cm-1.

Hemispherand-Strapped Calix[4]pyrrole: An Ion-pair Receptor for the Recognition and Extraction of Lithium Nitrite.

The hemispherand-strapped calix[4]pyrrole (1) acts as an ion pair receptor that exhibits selectivity for lithium salts. In organic media (CD2Cl2 and CD3OD, v/v, 9:1), receptor 1 binds LiCl with high preference relative to NaCl, KCl, and RbCl. DFT calculations provided support for the observed selectivity. Single crystal structures of five different lithium ion-pair complexes of 1 were obtained. In the case of LiCl, a single bridging water molecule between the lithium cation and chloride anion was observed, while tight contact ion pairs were observed in the case of the LiBr, LiI, LiNO3, and LiNO2 salts. Receptor 1 proved effective as an extractant for LiNO2 under both model solid-liquid and liquid-liquid extraction conditions.

Self-Assembled Pyridine-Dipyrrolate Cages.

An inherently nonlinear pyridine dipyrrolate ligand, namely 2,6-bis(3,4-diethyl-5-carboxy-1H-pyrrol-2yl)pyridine (compound 1), is able to distinguish between different zinc(II) cation sources, namely Zn(acac)2 and Zn(OAc)2, respectively. This differentiation is manifest both in terms of the observed fluorescent behavior in mixed organic media and the reaction chemistry. Treatment of 1 with Zn(acac)2 gives rise to a cage dimer, cage-1, wherein two molecules of compound 1 act as double bridging units to connect two individual cage subunits. As inferred from X-ray crystallographic studies, this cage system consists of discrete zinc dimers with hydroxide bridges that, with the assistance of bound DMF solvent molecules, serve to fix the geometry and orientation of the pyridine dipyrrolate building blocks. When a different zinc source, Zn(OAc)2, is used to carry out an ostensibly similar complexation reaction with compound 1, an acetate-bridged 1D abacus-like cage polymer is obtained as inferred from X-ray diffraction analysis. This extended solid state structure, cage-2, contains individual zinc dimer cage submits and appears stabilized by solvent molecules (DMF) and the counteranion (acetate). Rod-like assemblies are also observed by DLS and SEM. This construct, in contrast to cage-1, proved fluorescent in mixed organic media. The structure of the ligand itself (i.e., in the absence of Zn(II)) was confirmed by X-ray crystallographic analysis and was found to assemble into a supramolecular polymer. Conversion to a dimer form was seen upon the addition of TBAOAc. On the basis of the metric parameters, the structures seen in the solid state are stabilized via hydrogen bonding interactions involving solvent molecules.

Cyclopentadienyl capped thorium(IV) porphyrinoid complex.

The reaction between Th(IV) dipyriamethyrin dichloride and sodium cyclopentadienyl (Cp) results in the formation of a cyclopentadienyl capped thorium dipyriamethyrin complex, which to our knowledge represents the first expanded porphyrin f-element Cp complex.

A Decarboxylative Cross-Coupling Platform To Access 2-Heteroaryl Azetidines: Building Blocks with Application in Medicinal Chemistry.

Photoredox-transition metal dual catalysis provides a unique platform for constructing sp3-rich chemical matter. Here, we report a nickel-catalyzed cross-coupling of commercially available or easily prepared redox-active NHP azetidine-2-carboxylates with commercially available heteroaryl iodides to yield 2-heteroaryl azetidines. This "off-the-shelf" approach yielded products amenable to diversification giving access to novel saturated heterocyclic scaffolds useful for medicinal chemistry programs. An alternative mechanism for Hantzsch ester within nickel-catalyzed cross-coupling of heteroaryl halides and α-amino radicals is also presented.