Cyclic Ligands Research Articles

Back Cover: Next‐Generation Polymer Shells for Inorganic Nanoparticles are Highly Compact, Ultra‐Dense, and Long‐Lasting Cyclic Brushes (Angew. Chem. Int. Ed. 16/2017)

Next-generation shells for inorganic nanoparticles (NPs) are polymeric “shields” designed to last. In their Communication on page 4507 ff., E. M. Benetti et al. have demonstrated that when cyclic polymer ligands are grafted onto inorganic NPs, ultra-dense and highly compact brush shells are generated. Core-cyclic shell NPs are significantly more stable than their linear brush-functionalized counterparts and show full bio-inertness towards serum proteins.

Cyclic mu-opioid receptor ligands containing multiple N-methylated amino acid residues

In this study we report the in vitro activities of four cyclic opioid peptides with various sequence length/macrocycle size and N-methylamino acid residue content. N-Methylated amino acids were incorporated and cyclization was employed to enhance conformational rigidity to various extent. The effect of such modifications on ligand structure and binding properties were studied. The pentapeptide containing one endocyclic and one exocyclic N-methylated amino acid displayed the highest affinity to the mu-opioid receptor. This peptide was also shown to be a full agonist, while the other analogs failed to activate the mu opioid receptor. Results of molecular docking studies provided rationale for the explanation of binding properties on a structural basis.

Cyclic aminomethylphosphines as ligands. Rational design and unpredicted findings

Abstract: Rational design of title ligands and their transition metal complexes gave the high effective catalysts for hydrogen economy and perspective “stimuli-responsive” luminescent materials. Together with the above novel cyclic aminomehtylphospine ligands have showed a row of unpredicted properties like spontaneous formation of macrocyclic molecules, unique reversible slitting of macrocycles on to the smaller cycles, rapid interconversion of the isomers catalyzed by both acids and transitional metals, bridging behavior of usually chelating ligands and unexpected high influence of handling substituents on N-atoms on to the catalytic and luminescent properties of P-complexes.

Enantioselective Synthesis of Chiral Oxygen-Containing Heterocycles Using Copper-Catalyzed Aryl C-O Coupling Reactions via Asymmetric Desymmetrization.

An enantioselective desymmetric aryl C-O coupling reaction was demonstrated under the catalysis of CuI and a chiral cyclic diamine ligand. A series of chiral oxygen-containing heterocyclic units such as 2,3-dihydrobenzofurans, chromans, and 1,4-benzodioxanes with tertiary or quaternary stereocarbon centers were synthesized with this method. DFT calculations were also carried out for a better understanding of the model for enantiocontrol.

Bis(aminophosphine) diselenides as chemosensors for heavy metal cations: An electrochemical, spectroscopic and theoretical study

The synthesis of a new neutral bidentate ligand, bis(tetraethylselenophosphoramidoyl)methylamine, MeN[P(Se)(NEt2)2]2 (L1), was reported. A new cyclodiphosphazane ligand, [MeNP(Se)(NEt2)]2 (L2), was also isolated from the reaction mixture as a minor product. The title ligands were characterized by spectroscopic and electrochemical investigations. The electrochemical studies reveal that L1 is able to bind various heavy metallic cations (M2+: Zn2+, Cd2+, Pb2+, Hg2+ and Fe2+) forming very stable complexes. The addition of each cation led to important oxidation potential shifts up to 1070mV. However, the ligand L2 exhibited no sensitivity for any of the reported cations. In addition, DFT/B3LYP theoretical study was carried out and that unlike to the cyclic ligand L2, L1 is potentially able to chelate metal ions.

Synthesis and conformational analysis of peptides embodying 2,3-methanopipecolic acids.

The conformational analysis of linear and cyclic peptides incorporating 2,3-methanopipecolic acids (or Cyclopropane Pipecolic Acids, CPAs) as conformationally constrained α-amino acids is reported. Compared to peptides containing proline or pipecolic acid, a striking increase of the cis isomer (42-92%) around the CPA amide bond is observed, both in water and organic solvents, when these unnatural amino acids are embodied in linear amino acid sequences. The rotational barrier around the same bond in water was calculated, giving results comparable to that for the prolyl cis/trans isomerization. In organic solvents, CPAs at the i + 2 position of a peptide induce the formation of a type VIa β-turn secondary structure. When incorporated into a cyclic peptide, the cis geometry around the 2,3-methanopipecolic amide bond still prevails and, in the example studied herein (a cyclic RGD-containing ligand of αVβ3 integrin mimicking Cilengitide), conservation of the backbone geometry and side chain spatial orientation of the native peptide is also found. Given the importance of the proline cis/trans isomerism in many biological processes, CPAs could be useful as proline mimetics for probing protein-ligand interactions and generating novel bioactive compounds.

Methods of Assessing STING Activation and Trafficking.

The signaling adapter protein STING is crucial for the host immune response to cytosolic DNA and cyclic dinucleotides. Under basal conditions, STING resides on the endoplasmic reticulum (ER ) , but upon activation, it traffics through secretory pathway to cytoplasmic vesicles, where STING activates downstream immune signaling. Classical STING activation and trafficking are triggered by binding of cyclic dinucleotide ligands. STING signaling can also be activated by gain-of-function mutations that lead to constitutive trafficking of STING. These gain-of-function mutations are associated with several human diseases such as STING-associated vasculopathy with onset in infancy (SAVI), systemic lupus erythematosus (SLE), or familial chilblain lupus (FCL). This dynamic activation pathway presents a challenge to study. We describe methods here for measuring ligand-dependent and ligand-independent activation of STING signaling in HEK293T cells. We also describe a retroviral-based reconstitution assay to study STING protein trafficking and activation in immune competent cells such as mouse embryonic fibroblasts (MEF), which avoids the use of plasmid DNA. These methods will expedite research regarding STING trafficking and signaling dynamics in the settings of infection and autoimmune diseases.

Crown ether complexes of actinyls: a computational assessment of AnO2(15-crown-5)2+ (An = U, Np, Pu, Am, Cm).

For further fundamental understanding of the nature and extent of covalency in actinyl-ligand bonding, and the benefits that this may have in the design of new ligands for nuclear waste separation, there is burgeoning interest in the nature of actinyl complexes with polydentate or multiple-point-donor ligands, such as crown ethers. There are few cases of structurally authenticated molecular actinyl-crown bonds under ambient conditions. We report here the computational characterization of AnO22+-(15-crown-5) complexes, where An = U, Np, Pu, Am, and Cm, and 15-crown-5 is the cyclic polyether ligand with five ether oxygen atoms. In the gas-phase complex, the actinyl group is located inside of the crown ether, tilted slightly out of the plane of the five equatorial oxygen atoms that coordinate the actinide metal center. The actinyl-cyclic ether complexes are found to exhibit a conventional conformation, with typical An-Oaxial and An-Oequatorial distances and angles. A striking result is the enhanced stability of the insertion complex for UO22+versus NpO22+, PuO22+, AmO22+ and CmO22+, which is evaluated in the context of An-O binding strengths (esp. bonding covalency), and may have ramifications for the utility of actinyl-crown complexes in separation applications.

Crystal structure of (perchlorato-κO)(1,4,7,10-tetra-aza-cyclo-dodecane-κ4N)copper(II) perchlorate.

The crystal structure of the title salt, [Cu(ClO4)(C8H20N4)]ClO4, is reported. The CuII ion exhibits a square-pyramidal geometry and is coordinated by the four N atoms of the neutral 1,4,7,10-tetra-aza-cyclo-dodecane (cyclen) ligand and an O atom from one perchlorate anion, with the second perchlorate ion hydrogen-bonded to one of the amine N atoms of the cyclen ligand. Additional N-H⋯O hydrogen bonds between the amine H atoms and the coordinating and non-coordinating perchlorate groups create a three-dimensional network structure. Crystals were grown from a concentrated methanol solution at ambient temperature, resulting in no co-crystallization of solvent.

New Chiral Cyclic Sulfinamide–Olefin Ligands for Asymmetric 1,4-Additions

New Chiral Cyclic Sulfinamide–Olefin Ligands for Asymmetric 1,4-Additions

Synthesis of nickil (ii) complex of taazatricyclotetracosane (octc) macrocyclic complexes from the contaminated soil

Consumer demand for better quality produce is now on an increasing surge. In particular, some metals are not desirable in agriculture as they may harm the environment or humans. Because of this, the concentrations of metals in soils and foods should be regularly monitored. This paper extensively addresses our concerns about these undesired metals in the farm soil and farm produce and how to manage the situation so that it does not become a menace. This paper deals with the synthesis and characterization of macro cyclic ligand and its complex compound. Template condensation of chlorocarbons such as 1,1,2,2-tetrachloroethane with 1,3-diaminopropane in presence of nickel (II)) yielded the corresponding metal complexes such as 3,7,10,14,15,19,20,24- octaazatricyclotetracosane (OCTC). The macrocyclic ligands and their complexes have been characterized by elemental analysis, molecular weight determination, conductance, IR and NMR spectral studies. The magnetic moments, along with electronic spectral data suggested hexa coordinated state for Nickel, its geometry is outer orbit octahedral .Conductivity data suggests that they behave as electrolytes. The formulation of the complexes has been established on the basis of chemical composition. The significant ligand and their complexes have now widely being used as a catalyst in many industries.

Cyclic non-opioid dynorphin A analogues for the bradykinin receptors

Nerve injury and inflammation cause up-regulation of an endogenous opioid ligand, dynorphin A (Dyn A), in the spinal cord resulting in hyperalgesia via the interaction with bradykinin receptors (BRs). This is a non-opioid neuroexcitatory effect that cannot be blocked by opioid antagonists. Our systematic structure–activity relationships study on Dyn A identified lead ligands 1 and 4, along with the key structural feature (i.e. amphipathicity) for the BRs. However, the ligands showed very low metabolic stability in plasma (t1/2 <1h) and therefore, in order to improve their metabolic stabilities with retained biological activities, various modifications were performed. Cyclization of ligand 4 afforded a cyclic Dyn A analogue 5 that retained the same range of binding affinity as the linear ligand with improved metabolic stability (t1/2 >5h) and therefore possesses the potential as a pharmacophoric scaffold to be utilized for drug development.

Cyclic peptide ligand with high binding capacity for affinity purification of immunoglobulin G

The rapidly increasing implementation of antibodies in therapeutic and diagnostic applications has necessitated the development of antibody production and purification technologies for both academic and industrial usage. Bacterial Protein A and Protein G are known to bind antibodies with high affinity and have facilitated the isolation and purification thereof. Recently, small peptide ligands (i.e. IgG Fc domain-binding peptides, FcBP) that specifically bind to the Fc-domain of antibodies were reported. In the present study we describe the development of a reusable high affinity column for antibody purification utilizing immobilized FcBP, comprising 13 amino acids residues, on a sepharose resin. In addition to FcBP, Cys to Ser substituted FcBP (FcBP-Ser), reduced FcBP (FcBP-Red), commercial Protein A and Protein G resins, packed into columns, were evaluated for antibody purification. All these columns except the FcBP-Ser one showed good binding capacity for a humanized IgG (trastuzumab) and a chimeric IgG (cetuximab). The column packed with FcBP-Red allowed antibody purification at a less acidic pH (pH 4.8) than was required for the other ligand affinity columns used in our experiments (i.e., pH 3.2 for Protein G and FcBP columns, and pH 3.5 for Protein A column, respectively). Utilizing the FcBP column, antibodies from swine human sera were isolated with a purity of 95%. Interestingly, the FcBP column could be easily regenerated and operated without loss of efficiency for up to 60 runs, the maximum number of runs performed in the present study.

Heterovalent 2EuII/4EuIII and Trivalent 5EuIII Clusters Assembled with a Macrocyclic Cyclen Derivative Ligand: Molecular Structures, Oxidation Stabilities, and Luminescence Properties

Two coordination complexes EuII2EuIII4(OH)4(bza)4L2 (1) and EuIII5(H2O)(OH)4(NO3)3(bza)4L (2) have been assembled with the tetrasubstituted cyclen ligand N,N′,N′′,N′′′‐tetrakis(2‐hydroxy‐3‐methoxy‐5‐methylbenzyl)‐1,4,7,10‐tetraazacyclododecane (H4L) and the auxiliary ligand benzoic acid (Hbza). Complex 2 is a pentanuclear EuIII cluster whereas complex 1 is a huge heterovalent 2EuII/4EuIII cluster in which two divalent europium ions are trapped within the macrocyclic cavities of the designed ligands L and are further isolated from the environment by peripheral phenyl rings and the tetrahedral 4EuIII cluster, which results in the enhanced oxidative stability of Eu2+. The luminescence of complex 1 was investigated and is discussed in comparison with the luminescence of ligand H4L and complex 2. Owing to the protection of Eu2+ by the macrocyclic ligands L, the heterovalent complex exhibits a strong broad emission band with a maximum at 533 nm as well as the characteristic sharp emissions of Eu3+. The broad emission is redshifted compared with that of ligand H4L and has been attributed to the Laporte‐allowed 4f65d1 → 4f7 transition of Eu2+.

Synthesis and photophysical characterization of luminescent lanthanide complexes of nucleotide-functionalized cyclen- and dipicolinate-based ligands

Luminescent Eu(III)- and Tb(III)-complexes based on functionalized tetraazamacrocycle (cyclen) or dipicolinic acid (dpa) metal binding sites, and carrying 2′- or 5′-linked uridine moieties were prepared. The light-harvesting antennae were either a coumarin (in the cyclen-based architectures) or the dpa-moiety itself. Antenna excitation resulted in metal-centered emission for all complexes. The presence of the uridine resulted in less intense lanthanide emission compared to non-nucleotide-modified reference compounds. Nd(III)-complexes of cyclen ligands carrying a uridine but without a sensitizing antenna were also synthesized; these are envisioned as energy transfer acceptors to the Eu(III)-complexes. The possibility for Eu-to-Nd energy transfer was probed. The reported complexes are models for oligonucleotide-attached lanthanide probes.

Cyclic mismatch binding ligand CMBL4 binds to the 5'-T-3'/5'-GG-3' site by inducing the flipping out of thymine base.

A newly designed cyclic bis-naphthyridine carbamate dimer CMBL4 with a limited conformational flexibility was synthesized and characterized. Absorption spectra revealed that two naphthyridines in CMBL4 were stacked on each other in aqueous solutions. The most efficient binding of CMBL4 to DNA was observed for the sequence 5′-T-3′/5′-GG-3′ (T/GG) with the formation of a 1:1 complex, which is one of possible structural elements involved in the higher order structures of (TGG)n repeat DNA triggering the genome microdeletion. Surface plasmon resonance assay also showed the binding of CMBL4 with TGG repeat DNA. Potassium permanganate oxidation studies of CMBL4-bound duplex containing the T/GG site showed that the CMBL4-binding accelerated the oxidation of thymine at that site, which suggests the flipping out of the thymine base from a π-stack. Preferential binding was observed for CMBL4 compared with its acyclic variants, which suggests the marked significance of the macrocyclic structure for the recognition of the T/GG site.

Synthesis of Tröger's base derived ligands: PHZ-derivatized ligand with pendant donor arms

A cyclic diamine ligand whose core structure was derived from Tröger's base, and included additional pendant arms containing ancillary donor coordination sites was prepared and coordination with transition metals attempted.

Thermodynamically-Weighted Conformational Ensemble of Cyclic RGD Peptidomimetics from NOE Data.

In the case of flexible molecules, the standard approach of transforming NOE intensities into spatial restraints and of building conformational models minimizing these restraints greatly neglects the richness of molecular conformations. Making use of NOE intensities measured in triplicate and of an iterative molecular-dynamics scheme, we optimized a force field to generate a set of conformations whose ensemble is compatible with the experimental data, and is weighted according to the Boltzmann distribution. This scheme is applied to two cyclic peptidomimetic ligands of integrins. Their difference in binding affinity is recapitulated in terms of their difference in conformational fluctuations.

Development of the Double Cyclic Peptide Ligand for Antibody Purification and Protein Detection.

Development of a peptide-based affinity matrix and detection reagent is important for biomedical research and the biopharmaceutical industry. In the present work, we designed and synthesized an immunoglobin G (IgG)-binding peptide ligand, Fc-III-4C. Fc-III-4C is composed of 15 residues, and the 4 cysteine residues form 2 disulfide bonds to generate a double cyclic structure. The binding affinity of the Fc-III-4C peptide toward human IgG was determined to be 2.45 nM (Kd), which is higher than that of IgG with Protein A/G (Pro-A/G). Importantly, the Fc-III-4C peptide displayed high affinity to various IgGs from different species. Fc-III-4C immobilized agarose beads exhibited high stability and reusability when compared with that of the Pro-A/G-immobilized beads. The conjugate of Fc-III-4C with FITC was demonstrated to be suitable for immunofluorescence detection of proteins expressed in cells. These results demonstrate that the Fc-III-4C peptide is a useful affinity ligand for antibody purification and as a protein detection reagent.

Cyclic Opioid Peptides.

For decades the opioid receptors have been an attractive therapeutic target for the treatment of pain. Since the first discovery of enkephalin, approximately a dozen endogenous opioid peptides have been known to produce opioid activity and analgesia, but their therapeutics have been limited mainly due to low blood brain barrier penetration and poor resistance to proteolytic degradation. One versatile approach to overcome these drawbacks is the cyclization of linear peptides to cyclic peptides with constrained topographical structure. Compared to their linear parents, cyclic analogs exhibit better metabolic stability, lower offtarget toxicity, and improved bioavailability. Extensive structure-activity relationship studies have uncovered promising compounds for the treatment of pain as well as further elucidate structural elements required for selective opioid receptor activity. The benefits that come with employing cyclization can be further enhanced through the generation of polycyclic derivatives. Opioid ligands generally have a short peptide chain and thus the realm of polycyclic peptides has yet to be explored. In this review, a brief history of designing ligands for the opioid receptors, including classic linear and cyclic ligands, is discussed along with recent approaches and successes of cyclic peptide ligands for the receptors. Various scaffolds and approaches to improve bioavailability are elaborated and concluded with a discourse towards polycyclic peptides.