Dipicolylamine Research Articles

Development of a near-infrared fluorescent sensor with a large Stokes shift for sensing pyrophosphate in living cells and animals

The detection of pyrophosphate (PPi) in living systems has attracted considerable attention in recent years due to its biological significance. While many fluorescent PPi sensors were developed with emission changes in the visible region, near-infrared (NIR) fluorescent sensors for PPi are rather scarce. In this paper, a dicyanomethylene-benzopyran (DCMB) based phenol-bridged dinuclear Zn(II)-DPA (DPA: dipicolylamine) complex was prepared, which was found to be a promising NIR fluorescent sensor for PPi. This sensor features a remarkable large Stokes shift (>150 nm) and shows colorimetric and NIR fluorescence changes for PPi with high selectivity and sensitivity in 100% aqueous solution. The detection limit of this sensor for PPi was determined to be as low as 42 nM. In addition, this sensor exhibits low cytotoxicity and can be conveniently employed for bioimaging PPi in living cells and animals, indicating it has great potential for in vitro and in vivo detection of PPi.

Diisopropyl fluorophosphate (DFP) degradation activity using transition metal–dipicolylamine complexes

Transition metal complexes have been extensively used as catalysts for organophosphorus agent decomposition to reduce their toxicity with their performance being strongly dependent on the nature of the metal ion. To investigate this dependence, we prepared dipicolylamine (DPA)‐containing complexes of Cu(II), Zn(II), Ni(II), Co(II), and Fe(II) and analyzed their activities for the degradation of diisopropyl fluorophosphate (DFP), a nerve agent surrogate compound. Cu(II)‐DPA complex showed fastest reaction kinetics while Zn(II)‐DPA and Ni(II)‐DPA exhibited more slower reactions. This observation can be explained using frontier molecular orbital (FMO) theory, which revealed that the nucleophilicity of the oxygen atom in water molecules in these transition metal complexes was well matched with reactivity order observed in experiments. These investigations combined with theoretical study provide valuable information for designing and predicting the activity of new transition metal–organic ligand complexes as a catalyst to decompose and reduce toxicity of organophosphorus nerve agents.

Development of Dipicolylamine-Modified Cyclodextrins for the Design of Selective Guest-Responsive Receptors for ATP.

The construction of supramolecular recognition systems based on specific host–guest interactions has been studied in order to design selective chemical sensors. In this study, guest-responsive receptors for ATP have been designed with cyclodextrins (CyDs) as a basic prototype of the turn-on type fluorescent indicator. We synthesized dipicolylamine (DPA)-modified CyD–Cu2+ complexes (Cu·1α, Cu·1β, and Cu·1γ), and evaluated their recognition capabilities toward phosphoric acid derivatives in water. The UV-Vis absorption and fluorescence spectra revealed that Cu·1β selectively recognized ATP over other organic and inorganic phosphates, and that β-CyD had the most suitable cavity size for complexation with ATP. The 1D and 2D NMR analyses suggested that the ATP recognition was based on the host–guest interaction between the adenine moiety of ATP and the CyD cavity, as well as the recognition of phosphoric moieties by the Cu2+–DPA complex site. The specific interactions between the CyD cavity and the nucleobases enabled us to distinguish ATP from other nucleoside triphosphates, such as guanosine triphosphate (GTP), uridine triphosphate (UTP), and cytidine triphosphate (CTP). This study clarified the basic mechanisms of molecular recognition by modified CyDs, and suggested the potential for further application of CyDs in the design of highly selective supramolecular recognition systems for certain molecular targets in water.

Complexes of phosphonate and phosphinate derivatives of dipicolylamine

Phospho(i)nate derivatives of dipicolylamine show excellent selectivity for Zn(ii) over alkaline earth metal ions.

Electrostatic Modification for Promotion of Flavin-Mediated Oxidation of a Probe for Flavin Detection.

Electrostatic effects on the redox photochemistry of synthetic probes (1, 2, and 1-Zn) are examined by adjusting the thermodynamic driving force of their oxidation reactions. The redox photochemistry was simply controlled by introducing a zinc binding site (2,2'-dipicolylamine (DPA)) on the coumarin moiety of probe 2. Zinc complexation produced a positively charged environment on the coumarin (1-Zn), which lowered the electron density of a nearby 9 H-xanthene ring, attenuating the auto-oxidation of 1-Zn by 45 % compared with that of probe 1 at 298 K. The positive net charge of 1-Zn also provided an attractive Coulombic force toward the phosphate of flavin mononucleotide and flavin adenine dinucleotide, which lowered the reduction potential of the electron acceptor (isoalloxazine) and improved intermolecular electron transfer from the 9 H-xanthene ring to isoalloxazine. The flavin-mediated oxidation rate of 1-Zn was increased to 1.5 times that of probe 2. Probe 1-Zn showed highly selective sensing behaviour toward flavins, producing an intense brightness (ϵΦF =2.80×103 m-1 cm-1 ) in the long-wavelength regions (λmax =588 nm) upon flavin-mediated oxidation. Furthermore, probes 1-Zn and 2 were successfully applied to eosinophil imaging and the differential diagnosis of eosinophilia; this demonstrates their use as diagnostic tools.

Synthesis of novel coumarin nucleus-based DPA drug-like molecular entity: In vitro DNA/Cu(II) binding, DNA cleavage and pro-oxidant mechanism for anticancer action.

Despite substantial research on cancer therapeutics, systemic toxicity and drug-resistance limits the clinical application of many drugs like cisplatin. Therefore, new chemotherapeutic strategies against different malignancies are needed. Targeted cancer therapy is a new paradigm for cancer therapeutics which targets pathways or chemical entities specific to cancer cells than normal ones. Unlike normal cells, cancer cells contain elevated copper which plays an integral role in angiogenesis. Copper is an important metal ion associated with chromatin DNA, particularly with guanine. Thus, targeting copper via copper-specific chelators in cancer cells can serve as an effective anticancer strategy. New pharmacophore di(2-picolyl)amine (DPA)-3(bromoacetyl) coumarin (ligand-L) was synthesized and characterized by IR, ESI-MS, 1H- and 13C-NMR. Binding ability of ligand-L to DNA/Cu(II) was evaluated using a plethora of biophysical techniques which revealed ligand-L-DNA and ligand-L-Cu(II) interaction. Competitive displacement assay and docking confirmed non-intercalative binding mode of ligand-L with ctDNA. Cyclic voltammetry confirmed ligand-L causes quasi reversible Cu(II)/Cu(I) conversion. Further, acute toxicity studies revealed no toxic effects of ligand-L on mice. To evaluate the chemotherapeutic potential and anticancer mechanism of ligand-L, DNA damage via pBR322 cleavage assay and reactive oxygen species (ROS) generation were studied. Results demonstrate that ligand-L causes DNA cleavage involving ROS generation in the presence of Cu(II). In conclusion, ligand-L causes redox cycling of Cu(II) to generate ROS which leads to oxidative DNA damage and pro-oxidant cancer cell death. These findings will establish ligand-L as a lead molecule to synthesize new molecules with better copper chelating and pro-oxidant properties against different malignancies.

A selective luminescent sensor for the detection of copper (II) ions based on a ruthenium complex containing DPA moiety

A new ruthenium complex containing DPA (dipicolylamine) moiety, [Ru(phen)2(phdpa)]2+ (1) (phen=1, 10-phenanthroline; phdpa=5-(N,N-bis(2-picolyl)amino-methylene)-1, 10-phenanthroline) has been designed and synthesized as a highly selective and sensitive luminescent probe for the detection of Cu2+. The luminescence of complex 1 could be substantially quenched by the addition of copper ion. Complex 1 has a widely available pH range in 3–10 in aqueous solution and shows an excellent response selectivity to Cu2+. A detection limit of 1.55×10−7M was obtained.

A Fluorescent Probe for Pyrophosphate Based on Tetraphenylethylene Derivative with Aggregation‐Induced Emission Characteristics

AbstractIn this work, a fluorescent probe (TPE‐DPA) with aggregation‐induced emission (AIE) characteristics was prepared for detecting pyrophosphate (PPi) by attaching a dipicolylamine (DPA) unit into tetraphenylethylene (TPE) group. TPE‐DPA exhibits intense green emission in aqueous media because of the formation of the nanoaggregates. In the presence of Cu2+, the emission of TPE‐DPA can be effectively quenched due to the formation of complex TPE‐DPA/Cu2+. However, upon addition of PPi, the fluorescence can be selectively recovered because of the higher affinity between Cu2+ and PPi, and thus release of TPE‐DPA. The detection limit for PPi by using TPE‐DPA/Cu2+ is as low as 56 nM. Importantly, this strategy can be utilized for real‐time monitoring the alkaline phosphatase (ALP) activity and for imaging of PPi in living cells.

4-Connected azabicyclo[5.3.0]decane Smac mimetics-Zn2+ chelators as dual action antitumoral agents

Putative dual action compounds (DACs 3a–d) based on azabicyclo[5.3.0]decane (ABD) Smac mimetic scaffolds linked to Zn2+-chelating 2,2′-dipicolylamine (DPA) through their 4 position are reported and characterized. Their synthesis, their target affinity (cIAP1 BIR3, Zn2+) in cell-free assays, their pro-apoptotic effects, and their cytotoxicity in tumor cells with varying sensitivity to Smac mimetics are described. A limited influence of Zn2+ chelation on in vitro activity of DPA-substituted DACs 3a–d was sometimes perceivable, but did not lead to strong cellular synergistic effects. In particular, the linker connecting DPA with the ABD scaffold seems to influence cellular Zn2+-chelation, with longer lipophilic linkers/DAC 3c being the optimal choice.

A novel 3-Hydroxychromone fluorescence sensor for intracellular Zn2+ and its application in the recognition of prostate cancer cells

A novel fluorescent zinc sensor 3HC−DPA, containing a 3-hydroxychromone (3HC) chromophore and a zinc-selective metal chelator di(2-picolyl)amine (DPA), was prepared and found to chelate Zn2+ in a dimeric form. Due to the deprotonation of 3HC and occupation of the lone electron pairs on the nitrogen atoms of DPA, the complex [Zn2(3HC-DPA)2]2+ emitted sensitively and selectively strong fluorescence in solution. Moreover, cell experiments, including flow cytometry and two-photo excitation fluorescence microscopy, as well as inductively coupled plasma-atomic emission spectrometry (ICP-AES), demonstrated that 3HC-DPA possessed the ability to monitor intracellular free zinc ions in live cells. A promising use was developed for the ability of 3HC-DPA in the recognition of cancerous prostate cells from normal prostate cells, based on the added Zn2+ detection by flow cytometry and cell imaging.

Two-photon fluorescence sensors for imaging NMDA receptors and monitoring release of Zn2+ from the presynaptic terminal

Synaptic Zn2+ plays an important role in neurotransmission and a neuromodulator. The development of the imaging tools for monitoring spatiotemporal changes taking place in synaptic Zn2+ concentrations is necessary in order to understand the role of Zn2+ in the function of many aspects of the glutamate system. In this work, two-photon probes 1 and 2, bearing ifenprodil-like tails that have affinity for NMDA receptors of neuronal cells, were designed and prepared. The two-photon fluorescent probe 1, which bears (N-(6-acetylnaphthalen-2-yl)-N-methylglycine) as two-photon fluorophore, enables high resolution imaging of neuronal cells. The two-photon fluorescent probe 2, which contains the di-2-picolylamine (DPA) as a Zn2+-binding site, the naphthalimide unit as the two-photon fluorophore, and the ifenprodil-like tail as the NMDA receptor binding moiety, can be employed for selective detection of Zn2+ located near the NMDA receptor and for monitoring concentration changes of Zn2+ in live neurons and hippocampal tissues.

Nucleotide‐Independent Copper(II)‐Based Distance Measurements in DNA by Pulsed ESR Spectroscopy

A site-specific Cu2+ binding motif within a DNA duplex for distance measurements by ESR spectroscopy is reported. This motif utilizes a commercially available 2,2'-dipicolylamine (DPA) phosphormadite easily incorporated into any DNA oligonucleotide during initial DNA synthesis. The method only requires the simple post-synthetic addition of Cu2+ without the need for further chemical modification. Notably, the label is positioned within the DNA duplex, as opposed to outside the helical perimeter, for an accurate measurement of duplex distance. A distance of 2.7 nm was measured on a doubly Cu2+ -labeled DNA sequence, which is in exact agreement with the expected distance from both DNA modeling and molecular dynamic simulations. This result suggests that with this labeling strategy the ESR measured distance directly reports on backbone DNA distance, without the need for further modeling. Furthermore, the labeling strategy is structure- and nucleotide-independent.

Nucleotide‐Independent Copper(II)‐Based Distance Measurements in DNA by Pulsed ESR Spectroscopy

AbstractA site‐specific Cu2+ binding motif within a DNA duplex for distance measurements by ESR spectroscopy is reported. This motif utilizes a commercially available 2,2′‐dipicolylamine (DPA) phosphormadite easily incorporated into any DNA oligonucleotide during initial DNA synthesis. The method only requires the simple post‐synthetic addition of Cu2+ without the need for further chemical modification. Notably, the label is positioned within the DNA duplex, as opposed to outside the helical perimeter, for an accurate measurement of duplex distance. A distance of 2.7 nm was measured on a doubly Cu2+‐labeled DNA sequence, which is in exact agreement with the expected distance from both DNA modeling and molecular dynamic simulations. This result suggests that with this labeling strategy the ESR measured distance directly reports on backbone DNA distance, without the need for further modeling. Furthermore, the labeling strategy is structure‐ and nucleotide‐independent.

Engineered Zn(II)-Dipicolylamine-Gold Nanorod Provides Effective Prostate Cancer Treatment by Combining siRNA Delivery and Photothermal Therapy.

Combination cancer treatment has emerged as a critical approach to achieve remarkable anticancer effect. In this study, we prepared a theranostic nanoformulation that allows for photoacoustic imaging as well as combination gene and photothermal therapy. Gold nanorods (GNR) were coated with dipicolyl amine (DPA), which forms stable complexes with Zn2+ cations. The resulting nanoparticles, Zn(II)/DPA-GNR, recognize phosphate-containing molecules, including siRNA, because of the specific interaction between Zn(II) and the phosphates. We chose anti-polo-like kinase 1 siRNA (siPLK) as our example for gene silencing. The strong complexation between Zn(II)/DPA-GNR and siPLK provided high stability to the nano-complexes, which efficiently delivered siRNA into the targeted cancer cells in vitro and in vivo. The particle served as a theranostic agent because the GNRs of nano-complexes permitted effective photothermal therapy as well as photoacoustic imaging upon laser irradiation. This gene/photothermal combination therapy using siPLK/Zn(II)DPA-GNRs exhibited significant antitumor activity in a PC-3 tumor mouse model. The concept described in this work may be extended to the development of efficient delivery strategies for other polynucleotides as well as advanced anticancer therapy.

Synthesis of fluorescent naphthalimide-functionalized Fe3O4 nanoparticles and their application for the selective detection of Zn2+ present in contaminated soil

A fluorescent dopamine–naphthalimide–dipicolylamine (DPA) was synthesized as a sensing receptor for Zn2+. Naphthalimide-DPA (2) was immobilized onto the surface of iron oxide nanoparticle to prepare a hybrid nanomagnet 1-Fe3O4. Naphthalimide–DPA (2) and 1-Fe3O4 were observed to bind with Zn2+, leading to significant increase in fluorescence intensity at 527nm. The fluorescence increases of 2 (10μM) and 1-Fe3O4 (0.33wt%) by addition of Zn2+ were linear over the [Zn2+] range of 0–7μM and 0–20μM, respectively. These fluorescence changes were highly selective for Zn2+, which were readily monitored even in the presence of other competitive cations. In particular, 1-Fe3O4 exhibited an excellent limit of detection determined to be 0.0345 ppb. Furthermore, this system was found to be suitable for detecting Zn2+ in a wide pH range of 3–11 and could be reused with the addition of ethylenediaminetetraacetic acid (EDTA). Moreover, nanomagnet 1-Fe3O4 was employed for the selective detection and removal of Zn2+ from a soil sample. These results confirm that the use of 1-Fe3O4 is a novel and simple method for detecting Zn2+ in environmental samples.

Synthesis and preliminary biological evaluation of a 99m Tc-chlorambucil derivative as a potential tumor imaging agent.

Technetium-99m-based radiopharmaceuticals have been used widely as diagnostic agents in the nuclear medicine. Chlorambucil (CLB) as one typical alkylating drug exhibits excellent inhibition effects against many human malignancies. To develop and explore a novel potential imaging agent for early diagnosis of tumors, tricarbonyl technetium-99m and rhenium complexes on the basis of the tridentate ligand dipicolylamine (DPA) bound to the chlorambucil pharmacophore were designed and synthesized: 99m Tc-DPA-CLB (3) and Re-DPA-CLB (4). The high performance liquid chromatography analyses showed that the retention time of 3 and 4 was 13.5 and 13.6minutes, respectively. Radiolabeling efficiency of the 99m Tc-DPA-CLB tracer was 97%, and the radiochemical purity was larger than 95% after 6hours stored in phosphate buffered saline or human serum as observed by thin layer chromatography and high performance liquid chromatography. Biodistribution studies in a mouse model of breast cancer showed 99m Tc-DPA-CLB exhibited a favorable tumor affinity. The radiotracer cleared quickly in the first hour via hepatobiliary and renal routes of excretion, resulted in a very low background at 4hours post injection (p.i.). It had moderate uptake ratios of tumor to blood and tumor to muscle. These results suggested 99m Tc-DPA-CLB might be a promising SPECT imaging agent for tumor diagnosis.

Synthesis of Polyester Dendritic Scaffolds for Biomedical Applications.

Using a well-defined poly(2,2-bis(hydroxymethyl)propanoic acid) dendrimer scaffold, a series of G1 to G3 dendrons is functionalized at the periphery with alkynes to enable "Click" functionalization via the copper-catalyzed alkyne-azide cycloaddition (CuAAC). The resulting dendrons are further functionalized at the core with a dipicolylamine (DPA) moiety to enable radiolabeling with 99m Tc for molecular imaging applications. Efficient CuAAC coupling is achieved using an azide-functionalized triethylene glycol monomethyl ether (TEG-N3 ). Removal of copper from the DPA ligand is successfully performed on G1 and G2 dendrimers prior to radiolabeling with 99m Tc. Radiolabeling of the G3 dendrimer is accomplished via transmetallation of the [CuDPA]2+ ligand with 99m Tc, further demonstrating the feasibility of the synthetic strategies in the preparation of dendritic imaging agents. Subsequent attachment of an acyloxymethyl ketone (AOMK) derivative for targeting of cathepsin B is also explored. Despite demonstrating the ability to ligate multiple AOMK ligands, the AOMK-dendrimer conjugates are not able to bind to cathepsin B, which may be attributed to steric hindrance at the dendrimer periphery.

Novel 1,10-phenanthroline - di-2-picolylamine scaffold as a selective chemosensor for copper and cyanide ions

A new phenanthroline - di-2-picolylamine (DPA) conjugate 1 has been designed and synthesised with an aim to create greater bulk around phenanthroline N′s, hence excluding them from metal ion binding. Chemosensor 1 showed red shifted and increased absorbance with Cu2+ ions only upon examination for its recognition ability towards various cations. The selectivity displayed by the synthesised model compound 2 towards Cu2+ ions ascertained the participation of pyridine N′s of DPA as the major binding sites. The photophysical results have been well supported by the DFT calculations. Moreover, the addition of CN− ions to the 1-Cu2+ complex displaced Cu2+ from the complex, enabling estimation of CN− from the solution. Chemosensor 1 also exhibited moderate antibacterial activity towards Staphylococcus aureus and Streptococcus pneunomoniae.

A new fluorescence chemosensor for selective detection of copper ion in aqueous solution

A new fluorescent chemosensor based upon 2,5-diphenylfuran and di(2-picolyl)amine (DPA) was designed and synthesized. Its structure was confirmed by single crystal X-ray diffraction and its photophysical properties were studied by absorption and fluorescence spectra. This compound can be used to determine Cu2+ ion with high selectivity among a series of cations in aqueous DMSO. This sensor forms a 1:1 complex with Cu2+ and displays fluorescent quenching.

Dipicolylamine coupled rhodamine dyes: new clefts for highly selective naked eye sensing of Cu2+and CN−ions

The dipicolylamine (DPA) motif has been utilized in devising rhodamine labeled compounds1and2for Cu2+ions.