Peptide and peptidomimetic ligands for CXC chemokine receptor 4 (CXCR4)

The development of novel peptide and peptidomimetic ligands for the CXC chemokine receptor 4 (CXCR4) as therapeutic agents for HIV-1 infection, cancer, and immune system diseases has grown over the last decade. In this perspective article, the design of CXCR4 agonists and antagonists from endogenous stromal cell-derived factor-1 (SDF-1)/CXCL12 and horseshoe crab-derived antimicrobial peptides and their therapeutic and diagnostic applications are described.     

Heterocyclic dialdehydes: linkers in the synthesis of macroacyclic ligands

Macroacyclic heteroatomic podands containing one chelation cavity were obtained as a result of the biscondensation of diethyl 2-[(2-aminophenyl)aminomethylidene]malonate with heterocyclic dialdehy- des (2,5-thiophenedicarbaldehyde and 2,6-pyridinedicarbaldehyde).     

Design, synthesis, and validation of rigid linkers for bioactive peptides

Rigid linkers of variable length were synthesized and used to connect two NDP-α-MSH ligands. The linkers were incorporated by solid-phase synthesis. Biological evaluations indicate that there is virtually no effect of these linkers on ligand binding to the human melanocortin 4 receptor.     

Flexibility and sorption selectivity in rigid metal-organic frameworks: the impact of ether-functionalised linkers

The functionalisation of well-known rigid metal-organic frameworks (namely, [Zn(4)O(bdc)(3)](n), MOF-5, IRMOF-1 and [Zn(2)(bdc)(2)(dabco)](n); bdc = 1,4-benzene dicarboxylate, dabco = diazabicyclo[2.2.2]octane) with additional alkyl ether groups of the type -O-(CH(2))(n)-O-CH(3) (n = 2-4) initiates unexpected structural flexibility, as well as high sorption selectivity towards CO(2) over N(2) and CH(4) in the porous materials. These novel materials respond to the presence/absence of guest molecules with structural transformations. We found that the chain length of the alkyl ether groups and the substitution pattern of the bdc-type linker have a major impact on structural flexibility and sorption selectivity. Remarkably, our results show that a high crystalline order of the activated material is not a prerequisite to achieve significant porosity and high sorption selectivity.     

New chiral P-N ligands for the regio- and stereoselective Pd-catalyzed dimerization of styrene

Two new chiral, enantiomerically pure, hybrid P-N ligands, namely (2R,5S)-2-phenyl-3-(2-pyridyl)-1,3-diaza-2-phosphanicyclo[3,3,0]octan-4-one (1) and (2R,5S)-2-phenyl-3-(2-pyridyl)-1,3-diaza-2-phosphanicyclo[3,3,0]octane (2), have been synthesized starting from L-proline. The two ligands differ in the presence or not of a carbonyl group in the diazaphosphane ring. Their coordination chemistry towards Pd(II) was studied by reacting them with [Pd(CH?)Cl(cod)]. A different behaviour was observed: ligand 2 shows the expected bidentate chelating behaviour leading to the mononuclear Pd-complex, while ligand 1 acts as a terdentate ligand giving a dinuclear species. The corresponding cationic derivatives were obtained from the palladium neutral complexes, both as mono- and dinuclear derivatives, and tested as precatalysts for styrene dimerization, yielding E-1,3-diphenyl-1-butene regio- and stereoselectively as the sole product. A detailed analysis of the catalytic behaviour is reported.     

Synthesis of multi-1,10-phenanthroline ligands with 1,3-phenylene linkers and their lithium complexes

The synthesis of two multisite ligands containing four and five 1,10-phenanthroline (phen) chelates in line, respectively, is presented. The connectors are 1,3-phenylene linkers. The two ligands were prepared following multistep procedures, the two key reactions being the Suzuki coupling reaction between aromatic nuclei and the nucleophilic addition of aryllithium derivatives onto a phen fragment. The coordination chemistry of both ligands with Li+ ions was very clean and selective, whereas their reaction with copper(I) led to intractable mixtures of insoluble complexes. The tetraphen and the pentaphen compounds afforded almost quantitatively the four- and five-lithium double-stranded helical complexes, respectively. The helical systems are probably highly wound, as indicated by NMR measurements. The pronounced strain of the 5-Li+ complex is reflected by the easy loss of a lithium cation, as shown by electrospray mass spectrometry.     

NMR elucidation of some ligands derived from the pentacycloundecane skeleton

The complete NMR elucidation of three novel pentacycloundecane (PCU)-derived ligands is reported. 2D NMR techniques are used to overcome the problem of major overlapping of methine signals on the cage skeleton. The compounds were synthesized as potential ligands to be used in asymmetric catalysis. They represent the first instance where aromatic moieties have been attached directly to the cage skeleton using lithiation techniques. The X-ray crystal structure of one of the ligands was obtained. The X-ray structure was helpful in determining the potential NOESY interactions within the set of molecules. For the other ligands a high level Density Functional Theory (DFT) optimization was performed [B3LYP/6-31+g(d)] to visualize possible NOE interactions. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Computational elucidation of the transition state shape selectivity phenomenon

The most commonly cited example of a transition state shape selective reaction, m-xylene disproportionation in zeolites, is examined to determine if the local spatial environment of a reaction can significantly alter selectivity. In the studied reaction, ZPE-corrected rate limiting energy barriers are 136 kJ/mol for the methoxide-mediated pathway and 109 to 145 kJ/mol for the diphenylmethane-mediated pathway. Both pathways are likely to contribute to selectivity and disfavor one product isomer (1,3,5-trimethylbenzene), but relative selectivity to the other two isomers varies with pore geometry, mechanistic pathway, and inclusion of entropic effects. Most importantly, study of one pathway in three different common zeolite framework types (FAU, MFI, and MOR) allows explicit and practically oriented consideration of pore shape. Variation of the environment shape at the critical transition states is thus shown to affect the course of reaction. Barrier height shifts on the order of 10-20 kJ/mol are achievable. Observed selectivities do not agree with the transition state characteristics calculated here and, hence, are most likely due to product shape selectivity. Further examination of the pathways highlights the importance of mechanistic steps that do not result in isomer-defining bonds and leads to a more robust definition of transition state shape selectivity.     

Solid-phase synthesis of rigid acylpolyamines using temporary N-4,4'-dimethoxytrityl protection in the presence of trityl linkers

An N-protection protocol employing the 4,4'-dimethoxytrityl (Dmt) group in combination with borane reduction of resin-bound polyamides was shown to be an efficient methodology that enables synthesis of novel analogues of natural acylpolyamine toxins. Thus, three philanthotoxins containing polyamine chains with piperidyl and cyclohexyl structural elements, which introduce conformational rigidity, increased lipophilicity, and altered proteolytic properties, were obtained in 39-44% overall yield.     

Imaging agents for the chemokine receptor 4 (CXCR4)

The interaction between the chemokine receptor 4 (CXCR4) and stromal cell-derived factor-1 (SDF-1, also known as CXCL12) is a natural regulatory process in the human body. However, CXCR4 over-expression is also found in diseases such as cancer, where it plays a role in, among others, the metastatic spread. For this reason it is an interesting biomarker for the field of diagnostic oncology, and therefore, it is gaining increasing interest for applications in molecular imaging. Especially "small-molecule" imaging agents based on T140, FC131 and AMD3100 have been extensively studied. SDF-1, antibodies, pepducins and bioluminescence have also been used to visualize CXCR4. In this critical review reported CXCR4 targeting imaging agents are described based on their affinity, specificity and biodistribution. The level wherein CXCR4 is up-regulated in cancer patients and its relation to the different cell lines and animal models used to evaluate the efficacy of the imaging agents is also discussed (221 references).     

Synthesis and structural characterization of two copper complexes with long rigid ligands

Two copper complexes with long rigid ligands, Cu(Tta)₂(L¹) (I), and Cu(Tta)₂(L²) (II), where L₁ = (E)-3-(4-(1H-benzo[d]imidazol-1-yl)-(4-phenyl)phenyl)-1-phenylprop-2-en-1-one, L² = (E)-3-(4-(1H-imidazol-1-yl)phenyl)-1-(4-phenyl)phenyl)prop-2-en-1-one), have been synthesized and characterized. The single-crystal X-ray analysis (CIF files CCDC nos. 1409671 (I) and 1409672 (II)) for complexes I and II demonstrates that each copper ion assumes a distorted square-pyramidal MO₄N polyhedron in which four oxygen atoms come from the Tta ligands, and one nitrogen atom comes from the N-donor ligand. Both of the complexes are linked into 3D networks through weak intermolecular interactions.     

Easily immobilized di- and tetraphosphine linkers: rigid scaffolds that prevent interactions of metal complexes with oxide supports

Di- and tetraphosphines with rigid phenyl-, biphenyl-, and tetraphenylstannane, -silane, and -methane scaffolds, and various substituents R, have been synthesized and immobilized via triethoxysilane-propagated formation of one or two surface-bound phosphonium moieties. The remaining phosphine groups can be coordinated to metal complexes. All the detective work and proof is done by solid-state NMR spectroscopy.     

Gold nanocomposites with rigid fully conjugated heteroditopic ligands shell as nanobuilding blocks for coordination chemistry

Monodisperse and solvent adaptable gold nanoparticles stabilized by rigid and fully conjugated modified neocuproinium and terpyridinium salts have been characterized and further used as nanobuilding blocks for the synthesis of gold nanoparticles functionalized by polypyridyl ruthenium complexes.     

Calculated optoelectronic properties of ruthenium tris-bipyridine dyes containing oligophenyleneethynylene rigid rod linkers in different chemical environments

Ruthenium tris-bipyridine dyes containing oligophenyleneethynylene (OPE) rigid rod linker groups ([Ru(bpy)3]2+, [Ru(bpy)2bpy-E-Ipa]2+, [Ru(bpy)2bpy-E-Ph-E-Ipa]2+, and [Ru(bpy)2bpy-E-Bco-E-Ipa]2+, where bpy = 2,2'-bipyridine, E = ethynylene, Ph = p-phenylene, Bco = bicyclo[2.2.2]octylene, and Ipa = isophthalic acid) have been investigated using DFT and TD-DFT calculations to elucidate the influence of the rigid rod on their optoelectronic properties. Experimentally observed differences in the optical absorption for the different complexes are discussed on the basis of TD-DFT simulated absorption spectra. A comparison of the calculated optoelectronic properties of [Ru(bpy)2bpy-E-Ph-E-Ipa]2+ in different chemical environments, that is, in different solvents and with or without counter ions, suggests that both the absorption spectra and the redox properties of the dyes with OPE rods are sensitive to the environment. The calculations show that spurious low-energy charge-transfer excitations present in the TD-DFT calculations of the extended systems in vacuum are removed when the environment is included in the calculations.     

Assessing the suitability of 1,2,3-triazole linkers for covalent immobilization of chiral ligands: application to enantioselective phenylation of aldehydes

Alkynyl-functionalized amino alcohols have been covalently supported on azidomethylpolystyrene resins with different levels of functionalization through Cu(I)-catalyzed 1,3-dipolar cycloadditions ("click chemistry"). The resulting 1,2,3-triazole-substituted resins, characterized by different levels of ligand loading and, depending on the nature of the alkynyl-functionalized amino alcohol, the presence of a one-carbon, four-carbon, or eight-carbon linear spacer, have been tested as catalysts in the enantioselective phenyl transfer from zinc to aldehydes. High catalytic activities and enantioselectivities (up to 82% ee) have been recorded. The influence of structural characteristics of the resin on enantioselectivity are discussed, and the limitations in enantiocontrol inherent to the use of a 1,2,3-triazole linker have been rationalized with the help of DFT calculations on model systems.     

Isomerization of cyclobutane ligands in the solid state and solution

Cyclobutane compounds are a class of compounds that can be conveniently synthesized in the solid state by employing crystal engineering principles. The rctt-isomer (or the syn-dimer) is the most common form of any cyclobutene compound that is obtained in the solid state by the photochemical [2 + 2] cycloaddition reactions. However, these rctt-isomers can be converted to other less accessible forms, under some special conditions. Isomerization of cyclobutane compounds thus plays an important role in synthetic chemistry. Such isomerization of cyclobutane compounds have been reported in organic salts, metal complexes, coordination polymers and metal-organic frameworks. In this review, these fascinating examples of isomerization that occur both in the solid state and solution phase have been discussed.     

Oligomerization state of photosynthetic core complexes is correlated with the dimerization affinity of a transmembrane helix

In the Rhodobacter (Rba.) species of photosynthetic purple bacteria, a single transmembrane α-helix, PufX, is found within the core complex, an essential photosynthetic macromolecular assembly that performs the absorption and the initial processing of light energy. Despite its structural simplicity, many unresolved questions surround PufX, the most important of which is its location within the photosynthetic core complex. One proposed placement of PufX is at the center of a core complex dimer, where two PufX helices associate in the membrane and form a homodimer. Inability for PufX of certain Rba. species to form a homodimer is thought to lead to monomeric core complexes. In the present study, we employ a combination of computational and experimental techniques to test the hypothesized homodimerization of PufX. We carry out a systematic investigation to measure the dimerization affinity of PufX from four Rba. species, Rba. blasticus , Rba. capsulatus , Rba. sphaeroides , and Rba. veldkampii , using a molecular dynamics-based free-energy method, as well as experimental TOXCAT assays. We found that the four PufX helices have substantially different dimerization affinities. Both computational and experimental techniques demonstrate that species with dimeric core complexes have PufX that can potentially form a homodimer, whereas the one species with monomeric core complexes has a PufX with little to no dimerization propensity. Our analysis of the helix-helix interface revealed a number of positions that may be important for PufX dimerization and the formation of a hydrogen-bond network between these GxxxG-containing helices. Our results suggest that the different oligomerization states of core complexes in various Rba. species can be attributed, among other factors, to the different propensity of its PufX helix to homodimerize.     

Selective addition of CXCR3+CCR4-CD4+ Th1 cells enhances generation of cytotoxic T cells by dendritic cells in vitro

Increasing importance is being given to the stimulation of Th1 response in cancer immunotherapy because its presence can shift the direction of adaptive immune responses toward protective immunity. Based on chemokine receptor expression, CXCR3⁺CCR4^-CD4⁺ T cells as Th1-type cells were investigated its capacity in monocyte-derived dendritic cell (DC) maturation and polarization, and induction of antigen specific cytotoxic T lymphocytes (CTL) in vitro. The levels of IL-4, IL-5 and IL-10 were decreased to the basal level compared with high production of IFN-γ, TNF-α, and IL-2 in CXCR3⁺CCR4^-CD4⁺ T cells stimulated with anti-CD3 and anti-CD28 antibodies. Co-incubation of activated CD4⁺ or CXCR3⁺CCR4^-CD4⁺ T cells with DC (CD4⁺/DC or CXCR3⁺CD4⁺/DC, respectively) particularly up-regulated IL-12 and CD80 expression compared with DC matured with TNF-α and LPS (mDC). Although there was no significant difference between the effects of the CXCR3⁺CCR4^-CD4⁺ and CD4⁺ T cells on DC phenotype expression, CXCR3⁺CD4⁺/DC in CTL culture were able to expand number of CD8⁺ T cells and increased frequencies of IFN-γ secreting cells and overall cytolytic activity against tumor antigen WT-1. These results demonstrated that the selective addition of CXCR3⁺CCR4^-CD4⁺ T cells to CTL cultures could enhance the induction of CTLs by DC in vitro, and implicated on a novel strategy for adoptive T cell therapy.