Diazacrown Ethers Research Articles

Preparation of HOPO-containing lariate ethers based on the diaza-18-crown-6 scaffold

Cyclic and acyclic ligands containing the hydroxypyridinone (HOPO) moiety as donor group are known as strong coordinating compounds for a wide variety of metal ions. Based on the diaza-crown[18]ether Kryptofix K22, five different tendentate ligands were prepared using 1,2-HOPO, 1,2,3-HOPO and 2,3-Me-HOPO as additional binding moieties. The diaza-crown ether basic skeleton was furnished with two primary amine functions and subsequently reacted with the respective HOPO acids or the HOPO acid chlorides to obtain the desired HOPO derivatives in two synthesis steps after final deprotection. All compounds were evidenced by NMR and MS analyses.

Tumor targeted alpha particle therapy with an actinium-225 labelled antibody for carbonic anhydrase IX.

Selective antibody targeted delivery of α particle emitting actinium-225 to tumors has significant therapeutic potential. This work highlights the design and synthesis of a new bifunctional macrocyclic diazacrown ether chelator, H2MacropaSqOEt, that can be conjugated to antibodies and forms stable complexes with actinium-225. The macrocyclic diazacrown ether chelator incorporates a linker comprised of a short polyethylene glycol fragment and a squaramide ester that allows selective reaction with lysine residues on antibodies to form stable vinylogous amide linkages. This new H2MacropaSqOEt chelator was used to modify a monoclonal antibody, girentuximab (hG250), that binds to carbonic anhydrase IX, an enzyme that is overexpressed on the surface of cancers such as clear cell renal cell carcinoma. This new antibody conjugate (H2MacropaSq-hG250) had an average chelator to antibody ratio of 4 : 1 and retained high affinity for carbonic anhydrase IX. H2MacropaSq-hG250 was radiolabeled quantitatively with [225Ac]AcIII within one minute at room temperature with micromolar concentrations of antibody and the radioactive complex is stable in human serum for >7 days. Evaluation of [225Ac]Ac(MacropaSq-hG250) in a mouse xenograft model, that overexpresses carbonic anhydrase IX, demonstrated a highly significant therapeutic response. It is likely that H2MacropaSqOEt could be used to modify other antibodies providing a readily adaptable platform for other actinium-225 based therapeutics.

SYNTHESIS OF COMPLEXES OF DIAZACROWN ETHERS AND TRANSITION METALS AND INVESTEGATION OF THEIR BIOLOGICAL ACTIVITY

vazirova.leyla@gmail.com The synthesis of diazacrown ethers was carried out using efficient methods. New dibenzoazacrown ethers with functionally substituted hydroxyl and amino groups in the macrocyclic (MC) ring have been synthesized. The structure of the synthesized crown compounds - determined by IR mass NMR, -spectroscopy. Methods for the preparation of transition metal complexes with organic functional ligands based on diazacrown ethers having four, five, and six coordinating atoms in the rings. The synthesized new diazacrown ethers, due to hydroxyl and amino groups, increase the degree of intermolecular interactions and transfer from a two-dimensional structure to a three-dimensional one, which has an increased their biological activity. Keywords: Crown ethers, transition metals, biological activity,complex.

Dipodal Tetraamide Derivatives of 1,10-Diaza-18-Crown-6 and Alkylmalonic Acids-Synthesis and Use as Ionophores in Ion Selective Membrane Electrodes.

Novel dipodal derivatives of an 18-membered diaza-crown ether with two diamide chains featuring methylmalonic or butylmalonic acid residues were obtained and tested as ionophores in ion-selective plasticized membrane electrodes. The objective of the study was to identify measurement conditions which ensure the most favorable performance for magnesium ion-selective electrodes. The relationship between the molar lipophilic anion salt-to-ionophore ratio and selectivity of electrodes was examined. The best result was obtained for the conventional electrode containing Mg2 ionophore. Calculated selectivity coefficients were as follows: logKMg/Ca = −2.77, logKMg/Na = −3.46 and logKMg.K = −2.24 (SSM, 1M).

Synthesis, Biological Evaluation, and Molecular Modeling of Aza-Crown Ethers

Synthetic and natural ionophores have been developed to catalyze ion transport and have been shown to exhibit a variety of biological effects. We synthesized 24 aza- and diaza-crown ethers containing adamantyl, adamantylalkyl, aminomethylbenzoyl, and ε-aminocaproyl substituents and analyzed their biological effects in vitro. Ten of the compounds (8, 10–17, and 21) increased intracellular calcium ([Ca2+]i) in human neutrophils, with the most potent being compound 15 (N,N’-bis[2-(1-adamantyl)acetyl]-4,10-diaza-15-crown-5), suggesting that these compounds could alter normal neutrophil [Ca2+]i flux. Indeed, a number of these compounds (i.e., 8, 10–17, and 21) inhibited [Ca2+]i flux in human neutrophils activated by N-formyl peptide (fMLF). Some of these compounds also inhibited chemotactic peptide-induced [Ca2+]i flux in HL60 cells transfected with N-formyl peptide receptor 1 or 2 (FPR1 or FPR2). In addition, several of the active compounds inhibited neutrophil reactive oxygen species production induced by phorbol 12-myristate 13-acetate (PMA) and neutrophil chemotaxis toward fMLF, as both of these processes are highly dependent on regulated [Ca2+]i flux. Quantum chemical calculations were performed on five structure-related diaza-crown ethers and their complexes with Ca2+, Na+, and K+ to obtain a set of molecular electronic properties and to correlate these properties with biological activity. According to density-functional theory (DFT) modeling, Ca2+ ions were more effectively bound by these compounds versus Na+ and K+. The DFT-optimized structures of the ligand-Ca2+ complexes and quantitative structure-activity relationship (QSAR) analysis showed that the carbonyl oxygen atoms of the N,N’-diacylated diaza-crown ethers participated in cation binding and could play an important role in Ca2+ transfer. Thus, our modeling experiments provide a molecular basis to explain at least part of the ionophore mechanism of biological action of aza-crown ethers.

Demonstration of Selective Single-Barium Ion Detection with Dry Diazacrown Ether Naphthalimide Turn-on Chemosensors.

Single-molecule fluorescence imaging (SMFI) of gas-phase ions has been proposed for "barium tagging," a burgeoning area of research in particle physics to detect individual barium daughter ions. This has potential to significantly enhance the sensitivity of searches for neutrinoless double-beta decay (0νββ) that is obscured by background radiation events. The chemistry required to make such sensitive detection of Ba2+ by SMFI in dry Xe gas at solid interfaces has implications for solid-phase detection methods but has not been demonstrated. Here, we synthesized simple, robust, and effective Ba2+-selective chemosensors capable of function within ultrapure high-pressure 136Xe gas. Turn-on fluorescent naphthalimide-(di)azacrown ether chemosensors were Ba2+-selective and achieved SMFI in a polyacrylamide matrix. Fluorescence and NMR experiments supported a photoinduced electron transfer mechanism for turn-on sensing. Ba2+ selectivity was achieved with computational calculations correctly predicting the fluorescence responses of sensors to barium, mercury, and potassium ions. With these molecules, dry-phase single-Ba2+ ion imaging with turn-on fluorescence was realized using an oil-free microscopy technique for the first time-a significant advance toward single-Ba2+ ion detection within large volumes of 136Xe, plausibly enabling a background-independent technique to search for the hypothetical process of 0νββ.

Macrocyclic Chelates Bridged by a Diaza-Crown Ether: Towards Multinuclear Bimodal Molecular Imaging Probes

Bridged polymacrocyclic ligands featured by structurally different cages offer the possibility of coordinating multiple trivalent lanthanide ions, giving rise to the exploitation of their different physicochemical properties, e.g., multimodal detection for molecular imaging purposes. Intrigued by the complementary properties of optical and MR-based image capturing modalities, we report the synthesis and characterization of the polymetallic Ln(III)-based chelate comprised of two DOTA-amide-based ligands (DOTA—1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) bridged via 1,10-diaza-18-crown-6 (DA18C6) motif. The DOTA-amide moieties and the DA18C6 were used to chelate two Eu(III) ions and one Tb(III) ion, respectively, resulting in a multinuclear heterometallic complex Eu2LTb. The bimetallic complex without Tb(III), Eu2L, displayed a strong paramagnetic chemical exchange saturation transfer (paraCEST) effect. Notably, the luminescence spectra of Eu2LTb featured mixed emission including the characteristic bands of Eu(III) and Tb(III). The advantageous features of the complex Eu2LTb opens new possibilities for the future design of bimodal probes and their potential applicability in CEST MR and optical imaging.

The role of diazacrown ether in the enhancement of the biological activity ofsilver nanoparticles

The nanostructuring of hydroxyl-substituted diazacrown-ether (DC) by silver nanoparticles was obtained by green synthesis method in order to increase the antibacterial activity of silver nanoparticles. The synthesized DC, nanoparticles, and nanosupramolecular complex (Ag@DC) were studied by TEM, powder-XRD, and NMR, IR, and UV spectroscopy methods. The Ag@DC nanostructures were uniform and their sizes ranged from 8 to 18 nm. IR and UV spectra revealed the noncovalent formation of the nanosupramolecular complex. The antibacterial activities of the prepared active agents were investigated on gram-positive and gram-negative bacteria by twofold microdilution method. Ultrastructural study by TEM was performed on \textit{E. coli} BDU12 after treatment with Ag@DC. The results showed the improvement of the antibacterial action of Ag@DC compared to silver nanoparticles (E. coli BDU12 - 32 times, A. baumannii BDU32 - 16 times, K. pneumoniae BDU44 and P. aeruginosa BDU49 - 4 times, S. aureus BDU23 - 512 times). Chelating by DC significantly improved the antibacterial effects of the silver nanoparticles on gram-positive and gram-negative bacteria due to the ionophoric behavior of the crown ethers.

Synthesis and Complexation Studies of Optically Active Aza- and Diazacrown Ethers Containing a Pyrene Fluorophore Unit

Novel enantiopure azacrown [(R,R)-1 and (S,S)-1] and diazacrown [(R,R)-2–(R,R)-4 and (S,S)-2–(S,S)-4] ethers containing a pyrene fluorophore unit and two phenyl groups at their chiral centers were obtained in multistep syntheses. The action of these chemosensors is based on the photoinduced electron transfer (PET) process, thus they show fluorescence enhancement in the presence of protonated primary amines and amino acid esters. Their recognition abilities toward the enantiomers of 1-phenylethylamine hydrogen perchlorate (PEA), 1-(1-naphthyl) ethylamine hydrogen perchlorate (NEA), phenylglycine methyl ester hydrogen perchlorate (PGME), and phenylalanine methyl ester hydrogen perchlorate (PAME) were examined in acetonitrile using fluorescence spectroscopy.

A Compact-Cell Sensor based on Diazacrown Ether Derivative for the Determination of Ephedrine

A Compact-Cell Sensor based on Diazacrown Ether Derivative for the Determination of Ephedrine

Chiral cryptands possessing fragments of (S)-2,2′-diamino-1,1′-binaphtalene and diaza-crown ethers

A series of optically active macrobicyclic cryptands were obtained by the Pd0-catalyzed amination reaction between (S)-2,2′-diamino-1,1′-binaphtalene (BINAM) and N,N′-bis-(bromobenzyl) derivatives of diaza-crown ethers. The dependence of yields of the macrobicyclic products on the structure of the diaza-crown ether derivatives was demonstrated. A comprehensive study of the effects of a number of optically active amino alcohols on the fluorescence spectra of the prepared compounds was carried out.

Synthesis of polymacrocyclic compounds via Pd-catalyzed amination and evaluation of their derivatives as metal detectors

Abstract A mini-review is dedicated to the application of Pd(0)-catalyzed amination reactions for the synthesis of polymacrocyclic compounds of various architectures. Such molecules comprise diazacrown ether moieties or structural fragments of tri- and tetraazamacrocycles, polyamine or polyoxadiamine chains of different length and aromatic spacers. Polymacrocyclic compounds thus formed possess an increased number of coordination sites and are suitable for testing as potential receptors of metal cations. Some of these macrocyclic compounds were decorated with the exocyclic dansyl fluorophore group or were coupled with porphyrin units to form polymacrocyclic conjugates. Fluorescent spectra of these compounds were studied in the presence of various metal perchlorates and several macrocycles were found to act as chemosensors or molecular probes for such cations like Cu(II), Al(III), Cr(III).

Li+ and K+ ionic conductivity in ionic nematic liquid crystals based on 18-diaza-crown ether substituted with six decylalkoxy-p-cyanobiphenyl chains

Several ionic liquid crystals with different anions, based on coordination of K+ or Li+ to diaza-crown ether fragments, are spontaneously conductive without externally induced alignment.

A novel profluorescent paramagnetic diaza-crown ether: synthesis, characterization and alkaline metal-ion complexation.

Starting from Kryptofix 22 two different branches were covalently attached through the nitrogen atoms, one containing a fluorescent moiety and the other the stable free radical TEMPO. The novel derivative exhibits fluorescence and paramagnetic properties, while the diaza-crown part ensures the affinity for alkaline metal-ions.

A Fluorescent Sensor Array Based on Heteroatomic Macrocyclic Fluorophores for the Detection of Polluting Species in Natural Water Samples

The development of a novel all-solid-state optical sensor array based on heteroatomic macrocyclic fluorophores (diaza-crown ether, metallocorrole and pyridinophans) for the photographic analysis of liquid media, is presented. The sensitivity of the new optical system toward a number of different species (cations: Li+, K+, Na+, , Mg2+, Ca2+, Co2+, Cu2+, Zn2+, Cd2+, Pb2+ and anions: , , Cl−, Br−, ) was evaluated both in single selective sensor mode and in multisensory arrangement. The satisfactory PLS1 regression models between sensor array optical response and analyte concentration were obtained for Cd2+, Cu2+, Zn2+, and ions in all the range of tested concentrations. Among these species the highest attention was focused onto detection of cadmium and nitrite ions, for which the detection limits, DL, estimated by 3σ method were found 0.0013 mg/L and 0.21 mg/L respectively, and these values are lower than the corresponding WHO guideline values of 0.003 mg/L (Cd2+) and 2 mg/L (). The suitability of the developed sensors implemented with familiar devices for signal acquisition (Light Emitting Diode, LED, as light source and a digital camera as a signal detector), and chemometric methods for data treatment to perform fast and low-cost monitoring of species under interest, in real samples of environmental importance, is demonstrated.

Synthesis of Trimacrocyclic Compounds Comprising Diazacrown Ether Moieties via Pd(0)-Catalyzed Amination Reactions

Synthesis of Trimacrocyclic Compounds Comprising Diazacrown Ether Moieties via Pd(0)-Catalyzed Amination Reactions

Nuclease Activity of Diaza-Crown Ether Complexes of Cerium(III) with Different Functional Groups as Side Arms

Cerium(III) complexes of two ligands of a diaza-crown ether with different functional groups as side arms were synthesised and characterised. The catalytic ability of the cerium(III) complexes for pUC19 DNA cleavage was investigated and compared using agarose gel electrophoresis. The results indicate that the catalytic activity of the complex CeL2 [L2 = 2,2′- (1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-7,16-diyl) diacetamide] with two carbamoylmethyl groups is significantly higher than the complex CeL1 [L1 = 2,2′- (1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-7,16-diyl) diethanol] with two hydroxyethyl groups under the same conditions. The optimum catalytic concentrations of CeL1 and CeL2 were 7.69 × 10−5 and 3.08 × 10−5 mol L−1 respectively and excessively high concentrations of the complexes can reduce their catalytic efficiency due to the formation of inactive μ-hydroxo dimers. The optimum catalytic acidities of CeL1 and CeL2 were pH 7.0 and 7.5 respectively and excessively high pH of the reaction system can reduce the catalytic efficiency of the complexes due to the formation of cerium(III) hydroxide. DNA cleavage promoted by the two complexes takes place via the same hydrolytic pathway and so the activity difference of the two complexes is attributed to the stability of the complexes, rather than the catalytic mechanism.

A series of F-Element chelators; diaza crown ethers functionalized with catecholate binding substituents

Reported here is the preparation of azacrown ethers functionalized with catechol groups. The synthetic approach was (1st) novel in that it made use of the Mannich reaction and (2nd) valuable in that it provided an improved synthesis (in terms of practical deployment) of the known N,N′-bis(2,3-dihydroxybenzyl)-4,13-diaza-18-crown-6, H4ChaCha. Moreover, it demonstrated potential application of the synthetic method for accommodating a wide range of catecholate functionalities by using the synthetic strategy to prepare N,N′-bis(2,3-dihydroxy-5-tert-butylbenzyl)-4,13-diaza-18-crown-6 (H4tBu2ChaCha) for the first time. These H4ChaCha and H4tBu2ChaCha macrocycles offer exciting opportunity to expand redox chemistry for the f-elements. As “proof-of-principle,” we isolated the unusual tetrameric cluster [La2(tBuChaCha)2]2 from reactions between H4tBu2ChaCha and La[N(SiMe3)2]3. Characterization of [La2(tBuChaCha)2]2 by elemental analysis, single crystal X-ray diffraction, IR, and UV–vis–NIR spectroscopy suggested that the complex represented a rare example of an f-element semiquinone. It further demonstrated that the combination of La3+ and H4tBu2ChaCha provided access to one-electron oxidation chemistry within redox potential windows that were amenable to mild reaction conditions.

Synthesis of N- and O-Containing Macrobicycles with Central Biphenyl Moiety via Pd(0)-Catalyzed Amination Reactions

Background: Simple, efficient and enough versatile approaches to macrobicycles and macrotricycles, which are of great interest for the coordination of metal cations, were proposed in early 1990s using nucleophilic substitution reactions. Our research group was the first to begin a wide-range synthesis of N- and Ocontaining macrocycles using Pd-catalyzed amination reactions. Objective: The goal of the present research is to develop the catalytic synthesis of nitrogen- and oxygen containing macrobicycles organized around the central biphenyl moiety. Method: The method employed is the Pd(0)-catalyzed amination reactions which led to the formation of the first macrocycle comprising 3,3'-disubstituted biphenyl followed by the modification with two bromobenzyl moieties and the second Pd(0)-catalyzed macrocyclization which afforded target macrobicycles. Results: Macrocycles with the endocyclic 3,3'-disubstituted biphenyl moiety and diazadioxa, diazatrioxa, and tetraamine linkers were synthesized in 26-44% yields using Pd(0)-catalyzed amination reactions. They were modified with two 3-bromobenzyl substituents and introduced in the second Pd(0)-catalyzed macrocyclization to give macrobicycles in 8-27% yields. The result was shown to be dependent on the structure of the reacting compounds. The reaction with diazacrown ether provided a macrotricyclic derivative. Conclusion: An approach to a variety of N- and O-containing macrobicyclic compounds comprising a central biphenyl moiety and two oxadiamine (polyamine) chains via two consecutive Pd(0)-catalyzed amination reactions was elaborated.

Transition Metal Complexes of a Diaza-Crown Ether with two Carbamoylmethyl Substituents: Synthesis and Assessment as a Functional Nuclease

We report the synthesis, catalytic function and catalytic mechanism of two transition metal complexes (CuL, ZnL) of a diaza-crown ether with two acetylamino side arms [L = 2,2′-(1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-7,16-diyl)diacetamide] in the hydrolysis of DNA. Their nuclease functions on pUC19 DNA cleavage were investigated. The results indicated that the active species might be formed by the deprotonation of the water-coordinated molecules in the complex and the optimum pH is 8.0 for both CuL and ZnL. The catalytic activity of CuL is higher than that of ZnL in DNA hydrolytic cleavage due to the difference in the Lewis acidity of the central metal ions, which is contrary to the result with the Cu and Zn complexes of the parent ligand L0 (1,4,10,13-tetraoxa-7,16-diazacyclooctadecane) as artificial nuclease. Comparison studies of DNA cleavage in the presence and absence of several oxygen scavengers showed that these complexes can promote DNA cleavage by a hydrolytic pathway. Our proposed mechanism suggests that the negative charge on the phosphorus oxygen atom of the substrate molecule is dispersed and the intermediate is formed and stabilised by hydrogen bonding between the DNA molecule and the acetylamino group of the complex.