Dipicolylamine Research Articles

Polypeptide-Based Copper Ionophore for In Situ Glutathione-Triggered Chemodynamic and Chemotherapy.

Intracellular copper ion homeostasis has become an attractive target for cancer therapy. Herein, we report a 2,2'-dipicolylamine (DPA) functionalized polyglutamate derivative (PDHB) which is capable of rapidly forming PDHB-copper complex (PDHB@Cu) due to the strong coordination ability of pendant DPA with Cu2+. High drug loading content of doxorubicin (DOX) (>30 wt %) is realized due to the strong affinity of Cu2+ to DOX, while that is about 10 wt % for PDHB without Cu2+. The obtained PDHB@Cu-DOX can respond to specific endogenous stimuli (pH and glutathione (GSH)), releasing Cu2+ and DOX. The released DOX directly damages the DNA of tumor cells to cause apoptosis, while Cu2+ depletes intracellular GSH and is reduced to Cu+ simultaneously, which reacts with local H2O2 to produce highly toxic ·OH via a Fenton-like reaction, thus realizing synergistic chemodynamics and chemotherapy. This report provides an interesting polymeric ionophore strategy to deliver enough copper ions into cancer cells, which can also easily extend to other metal ions by replacing the ionophore components, thus having a wide application in nanomedicine.

Optimizing the Structure of a Pt Metal-Chelating Polymer to Reduce Nonspecific Binding for Mass Cytometry.

Mass cytometry is a bioanalytic tool based on atomic mass spectrometry for detecting biomarker expression on individual cells. Current reagents employ metal-chelating polymers binding isotopes of hard metal ions. Polymers bearing chelators for soft metal ions offer the promise for a large increase in multiplexing capabilities, but examples reported so far often have unacceptably high levels of nonspecific binding (NSB). We recently reported a new class of metal-chelating polymers with dipicolylamine (DPA) chelators that could bind Re and Pt. They also showed significant levels of NSB. Here, to reduce the NSB of the Pt-DPA polymer, we grafted water-soluble oligomers to the distal end of the dipicolylamine pendant group. Methoxy(polyethylene glycol) (DP = 24) was effective as was poly(sulfobetaine methacrylate) (DP = 29). Reacting the Pt-Cl bond of the metalated polymer with glutathione was remarkably effective at suppressing NSB. These results open the door to Pt-isotope-based metal-chelating polymers as new mass tags for mass cytometry.

Zinc-chelating BET bromodomain inhibitors equally target islet endocrine cell types.

Inhibition of the bromodomain and extraterminal domain (BET) protein family is a potential strategy to prevent and treat diabetes; however, the clinical use of BET bromodomain inhibitors (BETis) is associated with adverse effects. Here, we explore a strategy for targeting BETis to β cells by exploiting the high-zinc (Zn2+) concentration in β cells relative to other cell types. We report the synthesis of a novel, Zn2+-chelating derivative of the pan-BETi (+)-JQ1, (+)-JQ1-DPA, in which (+)-JQ1 was conjugated to dipicolyl amine (DPA). As controls, we synthesized (+)-JQ1-DBA, a non-Zn2+-chelating derivative, and (-)-JQ1-DPA, an inactive enantiomer that chelates Zn2+. Molecular modeling and biophysical assays showed that (+)-JQ1-DPA and (+)-JQ1-DBA retain potent binding to BET bromodomains in vitro. Cellular assays demonstrated (+)-JQ1-DPA attenuated NF-ĸB target gene expression in β cells stimulated with the proinflammatory cytokine interleukin 1β. To assess β-cell selectivity, we isolated islets from a mouse model that expresses green fluorescent protein in insulin-positive β cells and mTomato in insulin-negative cells (non-β cells). Surprisingly, Zn2+ chelation did not confer β-cell selectivity as (+)-JQ1-DPA was equally effective in both β and α cells; however, (+)-JQ1-DPA was less effective in macrophages, a nonendocrine islet cell type. Intriguingly, the non-Zn2+-chelating derivative (+)-JQ1-DBA displayed the opposite selectivity, with greater effect in macrophages compared with (+)-JQ1-DPA, suggesting potential as a macrophage-targeting molecule. These findings suggest that Zn2+-chelating small molecules confer endocrine cell selectivity rather than β-cell selectivity in pancreatic islets and provide valuable insights and techniques to assess Zn2+ chelation as an approach to selectively target small molecules to pancreatic β cells.NEW & NOTEWORTHY Inhibition of BET bromodomains is a novel potential strategy to prevent and treat diabetes mellitus. However, BET inhibitors have negative side effects. We synthesized a BET inhibitor expected to exploit the high zinc concentration in β cells to accumulate in β cells. We show our inhibitor targeted pancreatic endocrine cells; however, it was less effective in immune cells. A control inhibitor showed the opposite effect. These findings help us understand how to target specific cells in diabetes treatment.

Fine‐Tuning the Optoelectronic and Redox Properties of an Electropolymerized Thiophene Derivative for Highly Selective OECT‐Based Zinc Detection

AbstractOrganic mixed ionic‐electronic conductors (OMIEC) have emerged as pivotal materials in organic bioelectronics, particularly when integrated into organic electrochemical transistors (OECTs). Conducting polymer‐based devices have indeed demonstrated their capability to transduce biological signals into amplified output signals, harnessing the high transconductance of OECTs. The OECT operating principle and sensing capability strongly depend on ion‐conjugated backbone coupling: the dual nature of OMIECs, i.e. ion‐conductor and electron/hole‐conductor, presents an intrinsic interface in the bulk of the thin film across which transduction of ionic signals into electronic signals and vice versa occurs. Recent works have shown how selective sodium and potassium detection can be achieved by direct chemical modification of the polymer. Such modifications introduce ligands with affinity for the cations of interest as substituents on the polymer chain. The present work explores the integration of specifically modified conducting polymers into OECT channels, offering selectivity for zinc cations. Zinc fluxes are crucial in various biological processes, and their reliable detection, especially at low concentrations, is an important challenge. By electropolymerizing a thiophene‐based trimer, modified with a dipicolylamine (DPA) substituent, a conducting polymer‐based OECT is obtained that can selectively detect Zn2+ in the 10−6 to 10−3 mol L−1 concentration range in physiological buffers.

A new biphenol-dipicolylamine based ligand and its dinuclear Zn2+ complex as fluorescent sensors for ibuprofen and ketoprofen in aqueous solution.

In this work, the study of the new ligand 3,3'-bis[N,N-bis(pyridine-2-ylmethyl)aminomethyl]-2,2'-dihydroxybiphenyl (L) is reported, where a central 2,2'-biphenol (BPH) fluorophore was functionalized at 3,3'-positions with two dipicolylamine (DPA) side arms as receptor units. Following the synthesis and full chemical-physical characterization, the acid-base and Zn2+-coordination abilities of L were investigated through a combination of potentiometric, UV-Vis, fluorescence, NMR, XRD and DFT measurements. The optical properties of the ligand turned out to be strongly dependent on the pH, being straightforwardly associated with the protonation state of the BPH moiety, whereas its peculiar design allowed to form stable mono and dinuclear Zn2+ complexes. In the latter species, the presence of two Zn2+ ions coordinatively unsaturated and placed at close distance to each other, prompted us to test their usefulness as metallo-receptors for two environmental pollutants of great relevance, ibuprofen and ketoprofen. Potentiometric and fluorescence investigations evidenced that these important non-steroidal anti-inflammatory drugs (NSAIDs) are effectively coordinated by the metallo-receptors and, of relevance, both the stability and the fluorescence properties of the resulting ternary adducts are markedly affected by the different chemical architectures of the two substrates. This study aims at highlighting the promising perspectives arising from the use of polyamino phenolic ligands as chemosensors for H+/Zn2+ and other additional anionic targets in their metal-complexed forms.

A change in metal cation switches selectivity of a phospholipid sensor from phosphatidic acid to phosphatidylserine.

Phosphatidic acid and phosphatidylserine are anionic phospholipids with emerging signalling roles in cells. Determination of how phosphatidic acid and phosphatidylserine change location and quantity in cells over time requires selective fluorescent sensors that can distinguish these two anionic phospholipids. However, the design of such synthetic sensors that can selectively bind and respond to a single phospholipid within the complex membrane milieu remains challenging. In this work, we present a simple and robust strategy to control the selectivity of synthetic sensors for phosphatidic acid and phosphatidylserine. By changing the coordination metal of a dipicolylamine (DPA) ligand from Zn(II) to Ni(II) on the same synthetic sensor with a peptide backbone, we achieve a complete switch in selectivity from phosphatidic acid to phosphatidylserine in model lipid membranes. Furthermore, this strategy was largely unaffected by the choice and the position of the fluorophores. We envision that this strategy will provide a platform for the rational design of targeted synthetic phospholipid sensors to probe plasma and intracellular membranes.

Enhancing the antibacterial efficacy of vancomycin analogues: targeting metallo-β-lactamases and cell wall biosynthesis.

Vancomycin is a crucial last-resort antibiotic for tackling Gram-positive bacterial infections. However, its potency fails against the more difficult-to-treat Gram-negative bacteria (GNB). Vancomycin derivatives have shown promise as broad-spectrum antibacterials, but are still underexplored. Toward this, we present a novel strategy wherein we substitute the sugar moiety of vancomycin with a dipicolyl amine group, yielding VanNHdipi. This novel glycopeptide enhances its efficacy against vancomycin-resistant bacteria by up to 100-fold. A comprehensive approach involving microbiological assays, biochemical analyses, proteomics, and computational studies unraveled the impact of this design on biological activity. Our investigations reveal that VanNHdipi, like vancomycin, disrupts membrane-bound steps of cell wall synthesis inducing envelope stress, while also interfering with the structural integrity of the cytoplasmic membrane, setting it apart from vancomycin. Most noteworthy is its potency against critical GNB producing metallo-β-lactamases (MBLs). VanNHdipi effectively inactivates various MBLs with IC50 in the range of 0.2-10 μM resulting in resensitization of MBL-producing bacteria to carbapenems. Molecular docking and molecular dynamics (MD) studies indicate that H-bonding interactions between the sugar moiety of the vancomycin derivative with the amino acids on the surface of NDM-1 facilitate enhanced binding affinity for the enzyme. This work expands the scope of vancomycin derivatives and offers a promising new avenue for combating antibiotic resistance.

Metal Dipicolylamines and their Biomedical Applications: A Mini Review

Research in synthetic inorganic chemistry demonstrates that metal complexes are widely utilized as therapeutic as well as diagnostic agents. Due to the coordinative saturation, substitutional inertness, and unique redox characteristics, metal polypyridyl complexes have ignited attention and have been exploited in a number of biological and biomedical fields. The polypyridyl ligand, dipicolylamine (DPA) is a symmetrical secondary amine with two pyridyl rings. Delocalization of excited electrons occurs throughout the ligand system due to its conjugated character and the metal-to-ligand charge transfer transitions, resulting in a strong fluorescence signal. The high lipophilic nature of this ligand has proven to improve metal-DPA complex absorption by cell membranes. The N–H amine group in DPA and its analogues have the additional function of allowing hydrogen bonds to form, and deprotonation of this amine has allowed the creation of mononuclear and polynuclear species, with deprotonation of the bridging amine nitrogen also playing a significant role in the coordination sequence. DPA-appended metal complexes have garnered attention in the quest for linkages between magnetic, spectroscopic, structural, and coordination geometries. A number of mononuclear metal-DPA complex crystal structures with four, five, or six coordinated metal centers have been synthesized and explored for their biological properties. This study reviews DPA-derivatized ligand-linked metal complexes as promising cancer, microbial, and fungal inflammatory therapeutics, as well as potential diagnostic agents for fluorescence imaging and radiopharmaceuticals.
 Keywords: Dipicolylamine, metal complexes, coordination geometries, fluorescent agents

Dipicolylamine-Zn Induced Targeting and Photo-Eliminating of Pseudomonas aeruginosa and Drug-Resistance Gram-Positive Bacteria.

The emergence of drug-resistant bacteria, particularly resistant strains of Gram-negative bacteria, such as Pseudomonas aeruginosa, poses a significant threat to public health. Although antibacterial photodynamic therapy (APDT) is a promising strategy for combating drug-resistant bacteria, actively targeted photosensitizers (PSs) remain unknown. In this study, a PS based on dipicolylamine (DPA), known as WZK-DPA-Zn, is designed for the selective identification of P. aeruginosa and drug-resistant Gram-positive bacteria. WZK-DPA-Zn exploits the synergistic effects of DPA-Zn2+ coordination and cellular uptake, which could effectively anchor P. aeruginosa within a brief period (10min) without interference from other Gram-negative bacteria. Simultaneously, the cationic nature of WZK-DPA-Zn enhances its interaction with Gram-positive bacteria via electrostatic forces. Compared to traditional clinical antibiotics, WZK-DPA-Zn shows exceptional antibacterial activity without inducing drug resistance. This effectiveness is achieved using the APDT strategy when irradiated with white light or sunlight. The combination of WZK-DPA-Zn with Pluronic-based thermosensitive hydrogel dressings (WZK-DPA-Zn@Gel) effectively eliminates mixed bacterial infections and accelerates wound healing, thereby achieving a synergistic effect where "1+1>2." In summary, this study proposes a precise strategy employing DPA-Zn as the targeting moiety of a PS, facilitating the rapid elimination of P. aeruginosa and drug-resistant Gram-positive bacteria using APDT.

A mitochondria-targeted phosphorescent probe for sequentially detecting Cu2+ and cysteine and its imaging in living cells and in vivo

This study reported a unique mitochondria-targetable phosphorescent 'on-off-on' probe, Ir-DPA, based on an iridium(III) complex derivative for the sequential and specific detection of Cu2+ and Cys in vitro and in vivo. Probe Ir-DPA was constructed by a lipophilic cation unit as the chromophore as well as the mitochondria biomarker and a dipicolylamine (DPA) group as the recognition unit for Cu2+, followed by removal of Cu2+ specifically in the presence of Cys. The probe itself was strongly emissive at 570 nm. Upon addition of Cu2+, marked quenching occurred as result of the binding of Cu2+ with DPA moiety of this probe, accompanied by a distinct naked-eye luminescence color change from orange yellow to colorless. Additionally, further addition of Cys, the displacement of Cu2+ from in situ generated Ir-DPA-Cu ensemble because of the large nucleophilicity of cysteine toward Cu2+ led to the release of probe, giving rise to the luminescence recovery, as well as a relevant chromogenic change from colorless to orange yellow. Ir-DPA showed a large Stokes shift of 200 nm and high selectivity and sensitivity for the rapid detection of Cu2+ and Cys under physiological conditions, with low detection limits of 0.04 μM and 1.21 μM for Cu2+ and Cys, respectively. More importantly, the probe successfully targeted mitochondria, sensitively detected Cu2+ and exogenously or endogenously generated Cys both in mitochondria of living cells and zebrafish. Finally, Ir-DPA was capable of quantifying Cu2+ level in water samples and the in situ generated ensemble identifying Cys in human serum. These results indicated the great potential of Ir-DPA for monitoring Cu2+ and Cys in environmental, biological systems, and mitochondrial processes.

Development of a novel near-infrared fluorescent probe for selective detection of zinc ions in environmental and food samples

This study presents a novel near-infrared fluorescent probe TZn, which utilizes Dicyanoisophorone as the fluorophore and dipicolylamine (DPA) as the zinc ion recognition group. Selective recognition of zinc ions can be achieved in the near-infrared region（652 nm. And the chelation reaction of the probe TZn is verified through theoretical calculations and HPLC-MS. The probe TZn exhibits a large Stokes shift of 110 nm, a low detection limit (0.31 μM), and high selectivity. The probe TZn can also monitor the zinc ion in living cells and actual food samples.

Differential Activation and Desensitization States Promoted by Noncanonical α7 Nicotinic Acetylcholine Receptor Agonists.

A series of dipicolyl amine pyrimidines (DPPs) were previously identified as potential α7 agonists by means of a calcium influx assay in the presence of the positive allosteric modulator (PAM) 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl)-urea (PNU-120596). The compounds lack the quaternary or strongly basic nitrogens of typical nicotinic agonists. Although differing in structure from typical nicotinic agonists, based on crystallographic data with the acetylcholine binding protein, they appeared to engage the site shared by such typical orthosteric agonists. Using oocytes expressing human α7 receptors, we found that the DPPs were efficacious activators of the receptor, with currents showing rapid desensitization characteristic of α7 receptors. However, we note that the rate of recovery from this desensitization depends strongly on structural features within the DPP family. Although the activation of receptors by DPP was blocked by the competitive antagonist methyllycaconitine (MLA), MLA had no effect on the DPP-induced desensitization, suggesting multiple modes of DPP binding. As expected, the desensitized conformational states could be reactivated by PAMs. Mutants made insensitive to acetylcholine by the C190A mutation in the agonist binding site were weakly activated by DPPs. The observation that activation of C190A mutants by the DPP compounds was resistant to the allosteric antagonist (-)cis-trans-4-(2,3,5,6-tetramethylphenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide supports the hypothesis that the activity of these noncanonical agonists in the orthosteric binding sites was not entirely dependent on the classic epitopes controlling activation by typical agonists and that perhaps they may access alternative modes for promoting the conformational changes associated with activation and desensitization. SIGNIFICANCE STATEMENT: This study reports a family of nicotinic acetylcholine receptor agonists that break the rules about what the structure of a nicotinic acetylcholine receptor agonist should be. It shows that the activity of these noncanonical agonists in the orthosteric binding sites is not dependent on the classical epitopes controlling activation by typical agonists and that through different binding poses, they promote unique conformational changes associated with receptor activation and desensitization.

Three new turn-on fluorescent sensors for the selective detection of Zn2+: Synthesis, properties and DFT studies

The design and synthesis of three new 1,8-naphthalimide-based fluorescent sensors ( 1 – 3 ) for the detection of Zn 2+ in aqueous solution is described. The structural architect of these sensors contains 1,8-naphthalimide scaffold as a fluorophore attached to 2,2′-dipicolylamine (DPA) and bis(2-quinolinylmethyl)amine (DQA) receptors through an amide linkage. The addition of Zn 2+ to the solutions of sensors ( 1 – 3 ) led to enhanced fluorescence intensity, ranging between 2.5 and 14 folds. At physiological pH (pH = 7.4), these sensors exhibited high selectivities for Zn 2+ over a wide range of competing metal cations, displaying high sensitivities with a limit of detections of 120, 81.7 and 79.2 nM, respectively. This suggests that these sensors can detect chronic Zn 2+ concentration for freshwater ( > 1.84 μM), designated by the U.S. Environmental Protection Agency. DFT simulations performed on the more stable stacked conformations of unbound and Zn 2+ bounded states suggested that the latter display higher density of excited states than the unbound sensors. Moreover, the stacked conformer of sensor 3 was significantly more stable as compared to sensors 1 and 2 , which was attributed to a stronger Van Der Waals (VDW) interaction between DQA and 1,8-naphthalimide. The Zn 2+ binding leads to enhanced electronic coupling between the HOMOs and LUMOs, making excited states more populated which then undergoes geometric relaxation before emitting light and relaxing back to the ground states. The lower energy separation (5.0 eV) between the HOMO and the first Zn 2+ d-orbital in sensor 3 as compared to sensors 1 and 2 results in enhanced density of the generated states and subsequently higher intensity upon binding with Zn 2+ .

Zinc‐Chelating BET Bromodomain Inhibitors Selectively Accumulate and Affect Gene Expression in Pancreatic β‐Cells

The islets of Langerhans are a heterogeneous mixture of endocrine (hormone‐secreting) cells in the mammalian pancreas. Of particular interest are the β‐cells responsible for maintaining glucose homeostasis by secreting insulin in response to increased blood glucose. Type 1 diabetes (T1D) is characterized by autoimmune‐mediated destruction of β‐cells, resulting in an inability to produce and release insulin in response to changing glucose levels and subsequent reliance on daily insulin injections. There is currently no cure for T1D. The bromodomain and extra‐terminal domain (BET) family of proteins, comprised of BRD2, BRD3, BRD4 and BRDT, are a druggable family of proteins that can be targeted by pan‐BET bromodomain inhibitors (BETi), including the small molecule (+)‐JQ1. Recent studies have shown that targeting the BET family of proteins with BETi may prevent and treat T1D. However, the systemic use of current generation BETi is associated with off‐target, adverse effects including fatigue, gastrointestinal toxicity and memory loss. Since any treatment for T1D would be widely used in a pediatric patient population, avoiding off‐target effects is imperative. Here, we propose to ameliorate the off‐target effects of BET bromodomain inhibition by targeting BETi directly to pancreatic β‐cells. To achieve this, we exploited the high concentration of Zn2+ ions (~20 mM) present in β‐cells relative to other cells in the body. We report the synthesis of a novel, zinc‐chelating analogue of (+)‐JQ1, [(+)‐JQ1‐DPA], in which the BETi (+)‐JQ1 was conjugated, via an ethylenediamine linker, to dipicolyl amine (DPA). DPA chelates Zn2+ and thus enables (+)‐JQ1 to accumulate in β‐cells. As control compounds we also synthesized (+)‐JQ1‐DBA, a non‐zinc‐chelating analogue of (+)‐JQ1‐DPA, in which (+)‐JQ1 was conjugated to dibenzyl amine (DBA) and (‐)‐JQ1‐DPA, a zinc‐chelating compound that is inactive as a BETi. Molecular modeling and biophysical assays showed that (+)‐JQ1‐DPA and (+)‐JQ1‐DBA, but not (‐)‐JQ1‐DPA, retain binding to both bromodomains of BRD4 in vitro. Cellular assays demonstrated that (+)‐JQ1‐DPA retains efficacy; in particular, (+)‐JQ1‐DPA, attenuated the expression of NF‐ĸB target genes in β‐cells stimulated with the pro‐inflammatory cytokine, IL‐1β, a model for β‐cell destruction. Finally, using islets isolated from the INS1Cre; ROSA26mTmG mouse, an established mouse model that expresses enhanced green fluorescent protein in insulin‐positive cells and mTomato in insulin‐negative cells, we demonstrated that (+)‐JQ1‐DPA affects gene transcription in pancreatic β‐cells but not in other pancreatic cell types. In conclusion, we have synthesized a zinc‐chelating analogue of (+)‐JQ1 that is selectively active in pancreatic β‐cells over other islet cell types, including macrophages and α‐cells.

Zinc-Chelating Compounds as Inhibitors of Human and Bacterial Zinc Metalloproteases.

Inhibition of bacterial virulence is believed to be a new treatment option for bacterial infections. In the present study, we tested dipicolylamine (DPA), tripicolylamine (TPA), tris pyridine ethylene diamine (TPED), pyridine and thiophene derivatives as putative inhibitors of the bacterial virulence factors thermolysin (TLN), pseudolysin (PLN) and aureolysin (ALN) and the human zinc metalloproteases, matrix metalloprotease-9 (MMP-9) and matrix metalloprotease-14 (MMP-14). These compounds have nitrogen or sulfur as putative donor atoms for zinc chelation. In general, the compounds showed stronger inhibition of MMP-14 and PLN than of the other enzymes, with Ki values in the lower μM range. Except for DPA, none of the compounds showed significantly stronger inhibition of the virulence factors than of the human zinc metalloproteases. TPA and Zn230 were the only compounds that inhibited all five zinc metalloproteinases with a Ki value in the lower μM range. The thiophene compounds gave weak or no inhibition. Docking indicated that some of the compounds coordinated zinc by one oxygen atom from a hydroxyl or carbonyl group, or by oxygen atoms both from a hydroxyl group and a carbonyl group, and not by pyridine nitrogen as in DPA and TPA.

Mathematical Modeling of a Supramolecular Assembly for Pyrophosphate Sensing.

The power of sensing molecules is often characterized in part by determining their thermodynamic/dynamic properties, in particular the binding constant of a guest to a host. In many studies, traditional nonlinear regression analysis has been used to determine the binding constants, which cannot be applied to complex systems and limits the reliability of such calculations. Supramolecular sensor systems include many interactions that make such chemical systems complicated. The challenges in creating sensing molecules can be significantly decreased through the availability of detailed mathematical models of such systems. Here, we propose uncovering accurate thermodynamic parameters of chemical reactions using better-defined mathematical modeling-fitting analysis is the key to understanding molecular assemblies and developing new bio/sensing agents. The supramolecular example we chose for this investigation is a self-assembled sensor consists of a synthesized receptor, DPA (DPA = dipicolylamine)-appended phenylboronic acid (1) in combination with Zn2+(1.Zn) that forms various assemblies with a fluorophore like alizarin red S (ARS). The self-assemblies can detect multi-phosphates like pyrophosphate (PPi) in aqueous solutions. We developed a mathematical model for the simultaneous quantitative analysis of twenty-seven intertwined interactions and reactions between the sensor (1.Zn-ARS) and the target (PPi) for the first time, relying on the Newton-Raphson algorithm. Through analyzing simulated potentiometric titration data, we describe the concurrent determination of thermodynamic parameters of the different guest-host bindings. Various values of temperatures, initial concentrations, and starting pHs were considered to predict the required measurement conditions for thermodynamic studies. Accordingly, we determined the species concentrations of different host-guest bindings in a generalized way. This way, the binding capabilities of a set of species can be quantitatively examined to systematically measure the power of the sensing system. This study shows analyzing supramolecular self-assemblies with solid mathematical models has a high potential for a better understanding of molecular interactions within complex chemical networks and developing new sensors with better sensing effects for bio-purposes.

Tuned Cd2+ Selectivity: Showcase of Electronic and Regio-Effect of π-Extended Di-2-Picolylamine-Substituted Quinoline-Based Tolans.

π-Extended di-2-picolylamine (DPA)-substituted 8-hydroxyquinoline (8-HQ) tolans (2) were synthesized for testing electronic and regio-effects. The electron-poor CN-tolan (2b) showed clear selectivity for Cd2+ (>>Zn2+) over other metal ions via turn-on fluorescence, while the electron-rich MeO-tolan (2a) displayed no clear metal selectivity. Furthermore, considering that there was no significant energy difference between the Cd2+ complexes of 1 and 2b, the intended regio-effect (7- vs. 5-substituted effect) did not induce steric hindrance. Thus, the regio-effect is mainly electronic. Considering the above, 2a and 2b constitute a complete showcase in which electronic and regio-effects modulate the metal selectivity. The fluorescence titration of 2b (10 mM) with Cd2+ showed that the limit of detection (LOD) of the Cd2+-selective 2b was 158 nM in PBS (phosphate-buffered saline) (10 mM, pH 7.2) containing 50% MeOH.

Platinum(II)-Based Host-Guest Coordination-Driven Supramolecular Co-Assembly Assisted by Pt···Pt and π-π Stacking Interactions: A Dual-Selective Luminescence Sensor for Cations and Anions.

A cationic water-soluble dipicolylamine (DPA)-containing alkynylplatinum(II) terpyridine complex has been synthesized and employed as a dual-selective probe for the detection of cations and anions. The complex was shown to exhibit a strong binding affinity toward Zn2+, whereas the zinc-bound adduct was found to demonstrate the capability of recognizing pyrophosphate (PPi). As evidenced by molecular modeling and various spectroscopic and spectrometric studies, including HR-ESI mass spectrometry, NMR spectroscopy, PXRD measurements, and UV-vis absorption and emission spectroscopy, a PPi anion was found to be capable of bridging two zinc-bound complex molecules in a clip-shaped fashion, which was further oligomerized through intermolecular Pt···Pt and π-π stacking interactions to form nanofibers with a hexagonal columnar phase. This work provides important insights into not only the construction of aesthetically pleasing supramolecular architectures but also the multifunctional probes, which offer great promise to the fields of biosensing and chemical sensing.

Di(2-picolyl)amine-functionalized poly(ethylene glycol) hydrogels with tailorable metal–ligand coordination crosslinking

A new class of metallo-hydrogels has been developed using di(2-picolyl)amine (DPA)-functionalized 4-arm polyethylene glycol (4A-PEG-DPAn) polymers crosslinked by metal–ligand coordination.

Optical detection of di- and triphosphate anions with mixed monolayer-protected gold nanoparticles containing zinc(II)-dipicolylamine complexes.

Gold nanoparticles covered with a mixture of ligands of which one type contains solubilizing triethylene glycol residues and the other peripheral zinc(II)–dipicolylamine (DPA) complexes allowed the optical detection of hydrogenphosphate, diphosphate, and triphosphate anions in water/methanol 1:2 (v/v). These anions caused the bright red solutions of the nanoparticles to change their color because of nanoparticle aggregation followed by precipitation, whereas halides or oxoanions such as sulfate, nitrate, or carbonate produced no effect. The sensitivity of phosphate sensing depended on the nature of the anion, with diphosphate and triphosphate inducing visual changes at significantly lower concentrations than hydrogenphosphate. In addition, the sensing sensitivity was also affected by the ratio of the ligands on the nanoparticle surface, decreasing as the number of immobilized zinc(II)–dipicolylamine groups increased. A nanoparticle containing a 9:1 ratio of the solubilizing and the anion-binding ligand showed a color change at diphosphate and triphosphate concentrations as low as 10 μmol/L, for example, and precipitated at slightly higher concentrations. Hydrogenphosphate induced a nanoparticle precipitation only at a concentration of ca. 400 μmol/L, at which the precipitates formed in the presence of diphosphates and triphosphates redissolved. A nanoparticle containing fewer binding sites was more sensitive, while increasing the relative number of zinc(II)–dipicolylamine complexes beyond 25% had a negative impact on the limit of detection and the optical response. Transmission electron microscopy provided evidence that the changes of the nanoparticle properties observed in the presence of the phosphates were due to a nanoparticle crosslinking, consistent with the preferred binding mode of zinc(II)–dipicolylamine complexes with phosphate anions which involves binding of the anion between two metal centers. This work thus provided information on how the behavior of mixed monolayer-protected gold nanoparticles is affected by multivalent interactions, at the same time introducing a method to assess whether certain biologically relevant anions are present in an aqueous solution within a specific concentration range.