Chirality Sensing and Size Discrimination of Anions by Macrotricyclic Cyclen–Disodium Complexes

Two macrotricyclic ligands composed of two face-to-face octadentate metal chelates were synthesized. These cage-shaped disodium complexes had special recognition ability for various counter anions. Specific chiral dicarboxylates bound to the complexes within the cavity and exhibited chirality induction properties. For instance, N-Boc-Asp dianion strongly induced circular dichroism (CD) signals, but N-Boc-Glu dianion, which is one carbon longer, did not.     

Regioselective Bromination of a Thymine–Acridine Conjugate by N-Bromosuccinimide

A thymine and acridine conjugate (1), containing a benzylic carbon of thymine and an electron-rich aromatic ring (acridine) within the same molecule, was synthesized. Treatment of 1 with N-bromosuccinimide (NBS) in anhydrous chloroform in the presence of azobisisobutylnitrile produced a dibromo-substituted thymine–acridine conjugate (7) as a major product, in which the bromination was only observed on the acridine ring. Nuclear Overhauser effect (NOE) difference spectroscopy revealed that the actual bromination substitution was on C-2 and C-7 of acridine. Our results suggest that electrophilic aromatic substitution, not the expected benzylic radical reaction, takes place predominantly even when 1 is subjected to the NBS reaction condition, which favors radical processes. In addition, such selectivity is clearly solvent dependent.     

Spatiotemporally Coupled Photoactivity of Phthalocyanine–Peptide Conjugate Self-Assemblies for Adaptive Tumor Theranostics

Spatiotemporally coupled tumor phototheranostic platforms offer a flexible and precise system that takes the biological interaction between tumors and photoactive agents into consideration for optimizing treatment, which is highly consistent with precision medicine. However, the fabrication of monocomponent-based photoactive agents applicable to multifold imaging techniques and multiple therapies in a facile way remains challenging. In this study, we developed simple phthalocyanine–peptide (PF) conjugate-based monocomponent nanoparticles with spatiotemporally coupled photoactivity for adaptive tumor theranostics. The self-assembled PF nanoparticles possess well-defined spherical nanostructures and excellent colloidal stability along with supramolecular photothermal effects. Importantly, the PF nanoparticles showed switchable photoactivity triggered by their interactions with the cell membrane, which enables an adaptive transformation from photothermal therapy (PTT) and photoacoustic imaging (PAI) to photodynamic therapy (PDT) and corresponding fluorescence imaging (FI). Theranostic modalities are integrated in a spatiotemporally coupled manner, providing a facile, biocompatible and effective route for localized tumor phototherapy. This study offers a flexible and versatile strategy to integrate multiple theranostic modalities into a single component so that it can realize its full potential and thereby amplify its therapeutic efficacy, creating promising opportunities for the design of theranostics and further highlighting their clinical prospects to the diagnosis and treatment of cancers.     

Gold Ion–Angiotensin Peptide Interaction by Mass Spectrometry

Stimulated by the interest in developing gold compounds for treating cancer, gold ion–angiotensin peptide interactions are investigated by mass spectrometry. Under the experimental conditions used, the majority of gold ion–angiotensin peptide complexes contain gold in the oxidation states I and III. Both ESI-MS and MALDI-TOF MS detect singly/multiply charged ions for mononuclear/multinuclear gold-attached peptides, which are represented as [peptide + a Au(I) + b Au(III) + (e - a -3b) H]^e+, where a,b ≥ 0 and e is charge. ESI-MS data shows singly/multiply charged ions of Au(I)-peptide and Au(III)-peptide complexes. This study reveals that MALDI-TOF MS mainly detects singly charged Au(I)-peptide complexes, presumably due to the ionization process. The electrons in the MALDI plume seem to efficiently reduce Au(III) to Au(I). MALDI also tends to enhance the higher polymeric forms of gold-peptide complexes regardless of the laser power used. Collision-induced dissociation experiments of the mononuclear and dinuclear gold-attached peptide ions for angiotensin peptides show that the gold ion (a soft acid) binding sites are in the vicinity of Cys (a soft ligand), His (a major anchor of peptide for metal ion chelation), and the basic residue Arg. Data also suggests that the abundance of gold-attached peptides increases with higher gold concentration until saturation, after which an increase in gold ion concentration leads to the aggregation and/or precipitation of gold-bound peptides.     

Sensing abilities of materials prepared by sol–gel technology

The advantages of the sol–gel technology are undoubtedly simplicity and versatility. It enables to obtain for example oxides in the form of layers, powders, monoliths or fibers. These materials can be successfully applied for sensing purposes due to their properties such as transparency, porosity, and high surface areas. In this article, the basis of operation of mainly optical and semiconductor sensors are presented. A brief overview of various kinds of sensors is submitted. The utility of optical fibers and planar waveguides in these systems is discussed. The paper contains also some results obtained by the authors in the field of thin film-based sensors.     

Discrete π Stack of a Tweezer-Shaped Naphthalenediimide–Anthracene Conjugate

The design and synthesis of a tweezer-shaped naphthalenediimide (NDI)–anthracene conjugate ( 2NDI ) are reported. In the structure of the closed form (π_NDI ⋅⋅⋅ π_NDI stack) of 2NDI , which was elucidated by single-crystal XRD, the existence of C−H ⋅⋅⋅ O hydrogen bonding involving the nearest carbonyl oxygen atom of an NDI unit was suggested. The tunability of π_NDI ⋅⋅⋅ π_NDI interactions was studied by means of UV/Vis absorption, fluorescence and NMR spectroscopy and molecular modelling. This revealed that the π_NDI ⋅⋅⋅ π_NDI interactions in 2NDI affect the absorption and emission properties depending on the temperature. Furthermore, in polar solvents, 2NDI prefers the stronger π_NDI ⋅⋅⋅ π_NDI stack, whereas the π_NDI ⋅⋅⋅ π_NDI interaction is diminished in nonpolar solvents. Importantly, the conformational variations of 2NDI can be reversibly switched by variation in temperature, and this suggests potential application for fluorogenic molecular switches upon temperature changes.     

Tuning the Topological Landscape of DNA–Cyclodextrin Nanocomplexes by Molecular Design

Original molecular vectors that ensure broad flexibility to tune the shape and surface properties of plasmid DNA (pDNA) condensates are reported herein. The prototypic design involves a cyclodextrin (CD) platform bearing a polycationic cluster at the primary face and a doubly linked aromatic module bridging two consecutive monosaccharide units at the secondary face that behaves as a topology-encoding element. Subtle differences at the molecular level then translate into disparate morphologies at the nanoscale, including rods, worms, toroids, globules, ellipsoids, and spheroids. In vitro evaluation of the transfection capabilities revealed marked selectivity differences as a function of nanocomplex morphology. Remarkably high transfection efficiencies were associated with ellipsoidal or spherical shapes with a lamellar internal arrangement of pDNA chains and CD bilayers. Computational studies support that the stability of such supramolecular edifices is directly related to the tendency of the molecular vector to form noncovalent dimers upon DNA templating. Because the stability of the dimers depends on the protonation state of the polycationic clusters, the coaggregates display pH responsiveness, which facilitates endosomal escape and timely DNA release, a key step in successful transfection. The results provide a versatile strategy for the construction of fully synthetic and perfectly monodisperse nonviral gene delivery systems uniquely suited for optimization schemes.     

Display Selection of a Hybrid Foldamer–Peptide Macrocycle

Expanding the chemical diversity of peptide macrocycle libraries for display selection is desirable to improve their potential to bind biomolecular targets. We now have implemented a considerable expansion through a large aromatic helical foldamer inclusion. A foldamer was first identified that undergoes flexizyme-mediated tRNA acylation and that is capable of initiating ribosomal translation with yields sufficiently high to perform an mRNA display selection of macrocyclic foldamer–peptide hybrids. A hybrid macrocyclic nanomolar binder to the C-lobe of the E6AP HECT domain was selected that showed a highly converged peptide sequence. A crystal structure and molecular dynamics simulations revealed that both the peptide and foldamer are helical in an intriguing reciprocal stapling fashion. The strong residue convergence could be rationalized based on their involvement in specific interactions with the target protein. The foldamer stabilizes the peptide helix through stapling and through contacts with key residues. These results altogether represent a significant extension of the chemical space amenable to display selection and highlight possible benefits of inserting an aromatic foldamer into a peptide macrocycle for the purpose of protein recognition.     

Mapping a Noncovalent Protein–Peptide Interface by Top-Down FTICR Mass Spectrometry Using Electron Capture Dissociation

Noncovalent protein–ligand and protein–protein complexes are readily detected using electrospray ionization mass spectrometry (ESI MS). Furthermore, recent reports have demonstrated that careful use of electron capture dissociation (ECD) fragmentation allows covalent backbone bonds of protein complexes to be dissociated without disruption of noncovalent protein–ligand interactions. In this way the site of protein–ligand interfaces can be identified. To date, protein–ligand complexes, which have proven tractable to this technique, have been mediated by ionic electrostatic interactions, i.e., ion pair interactions or salt bridging. Here we extend this methodology by applying ECD to study a protein–peptide complex that contains no electrostatics interactions. We analyzed the complex between the 21 kDa p53-inhibitor protein anterior gradient-2 and its hexapeptide binding ligand (PTTIYY). ECD fragmentation of the 1:1 complex occurs with retention of protein–peptide binding and analysis of the resulting fragments allows the binding interface to be localized to a C-terminal region between residues 109 and 175. These finding are supported by a solution-phase competition assay, which implicates the region between residues 108 and 122 within AGR2 as the PTTIYY binding interface. Our study expands previous findings by demonstrating that top-down ECD mass spectrometry can be used to determine directly the sites of peptide–protein interfaces. This highlights the growing potential of using ECD and related top-down fragmentation techniques for interrogation of protein–protein interfaces.     

Peptide Macrocyclization Catalyzed by a Prolyl Oligopeptidase Involved in α-Amanitin Biosynthesis

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Studies on Cyclodextrin Inclusion Complex by Fluorescence Anisotropy

An equation for determining the equilibrium association constant (KA) of cyclodextrin inclusion complex with fluorescence anisotropy is derived and used to determine KA of pyrene-B-cyclodextrin inclusion complex. The existing forms of cyclodextrin inclusion complex in solution, the interaction type of host with guest, and the possibility of application of B-cyclodextrin in the analysis of metal ions using naphthalene derivative as a ligand are discussed based on the equation derived along with the curve of fluorescence anisotropy versus cyclodextrin concentration of guest/cyclodextrin system.     

Conformational Panorama and Chirality Controlled Structure–Energy Relationship in a Chiral Carboxylic Acid Dimer

Chirality recognition in dimers of tetrahydro-2-furoic acid (THFA) was studied in a conformer-specific manner using rotational spectroscopy and theoretical approaches. THFA shows a strong preference for the trans- over the cis-COOH configuration. Two drastically different scenarios are possible for the detectable (THFA)₂: a kinetically preferred dimer bound by feeble interactions between two trans THFAs or a thermodynamically favored dimer with a double hydrogen-bonded ring structure between two cis subunits. To identify the conformers responsible for the extremely dense rotational spectra observed, it was essential not only to locate several hundred homo/heterochiral (THFA)₂ minima in ab initio calculations but also to evaluate the energetic connectivities among the minima. The study further reveals an interesting chirality dependent structure–energy ordering relationship. A method for enantiomeric excess (ee) determination of THFA is presented using a recently proposed chiral self-tag approach.     

X-ray Crystallographic Observation of Chiral Transformations within a Metal–Peptide Pore

Porous metal complexes enable single-crystal X-ray crystallographic observation of included guests or reaction intermediates through simple soaking with the guests/substrates. Previous studies on this technique have often encountered difficulties in the observation of chiral structures because the host frameworks had no chirality. We synthesized a new metal–peptide porous complex through a folding-and-assembly strategy and utilized the chiral pore for trapping chiral guests. Chiral alcohols and ketones were successfully included within the pore. Crystallographic analyses clearly revealed not only their chemical structures but also chiral transformation events within the pore such as fixed conformations or an unstable hemiacetal formation.     

Hexabenzocoronene Graphitic Nanocoils Appended with Crown Ethers: Supramolecular Chirality Induced by Host–Guest Interaction

We have designed and synthesized two new achiral hexa-peri-hexabenzocoronene (HBC) derivatives, HBC^CE and HBC^TEG-CE , which bear the crown ether as the pendant for the amino acid binding site. The HBC^CE self-assembled into a racemic mixture of P- and M-handed helical nanocoils, however, in the presence of chiral amino acid guests, it formed helical nanocoils with one-handed screw sense. The effects of the concentration, type and configuration of the guests on the induced circular dichroism (ICD) during the co-assembly of HBC^CE with chiral amino acids were also investigated. Additionally, after complete removal of the chiral guests, the optically active nanocoils did not racemize, even in the presence of excess amino acids with the opposite configuration. In contrast, HBC^TEG-CE with a long triethylene glycol (TEG) chain between the crown ether group and the HBC unit did not exhibit ICD during the co-assembly with chiral amino acids.     

Conjugate addition of unactivated thiols to α,β-unsaturated ketones catalyzed by a bifunctional rhenium(V)–oxo complex

ReOCl₃(OPPh₃)(S(CH₃)₂) has been found to be an efficient bifunctional catalyst for the 1,4-addition of thiols to α,β-unsaturated ketones. The addition of thiophenol derivatives and alkyl thiols proceeds under mild reaction conditions without pre-activation of the thiol or exogenous base. Reactions of aryl, alkyl, and cyclic enones produce the corresponding β-sulfanyl ketones in good to excellent yield.     

Structure-Guided Design of a Group B Streptococcus Type III Synthetic Glycan–Conjugate Vaccine

Identification of glycan functional epitopes is of paramount importance for rational design of glycoconjugate vaccines. We recently mapped the structural epitope of the capsular polysaccharide from type III Group B Streptococcus (GBSIII), a major cause of invasive disease in newborns, by using a dimer fragment (composed of two pentasaccharide repeating units) obtained by depolymerization complexed with a protective mAb. Although reported data had suggested a highly complex epitope contained in a helical structure composed of more than four repeating units, we showed that such dimer conjugated to a carrier protein with a proper glycosylation degree elicited functional antibodies comparably to the full-length conjugated polysaccharide. Here, starting from the X-ray crystallographic structure of the polysaccharide fragment–mAb complex, we synthesized a hexasaccharide comprising exclusively the relevant positions involved in binding. Combining competitive surface plasmon resonance and saturation transfer difference NMR spectroscopy as well as in-silico modeling, we demonstrated that this synthetic glycan was recognized by the mAb similarly to the dimer. The hexasaccharide conjugated to CRM₁₉₇, a mutant of diphtheria toxin, elicited a robust functional immune response that was not inferior to the polysaccharide conjugate, indicating that it may suffice as a vaccine antigen. This is the first evidence of an X-ray crystallography-guided design of a synthetic carbohydrate-based conjugate vaccine.     

Synthesis of Novel Cyclodextrin Dimers Linked by Multidentate Coordination Units

Cyclodextrins(CDs)ethibitmolccularrecognitionandinclusioncatalysiswhichresemblethatofenzyInes,'buttheirbindingabilitiestoguestmoleculesareusuallyweaker.OnewayofsolvingthisproblemistointroduceanotherCDasanadditionalbindingsitetoformaCDdimer.SuperiortosingleCDderivativesinmolecularrecognitionandbindingabilitytosubstrate,theserecentlyemergingCDdimersareshowingprondseasmoresophisticatedenZymembocs.2AnumberofCDdimershavebeenpreparedtoinvestigatethebindingpropertiestoguestmolecules.However,syn…     

Selective Array-Based Sensing of Anabolic Steroids in Aqueous Solution by Host–Guest Reporter Complexes

Arrayed complexes of a water-soluble deep cavitand and two fluorescent indicators show selective sensing of anabolic-androgenic steroids in aqueous environments. By combining the host–guest complexes with small amounts of heavy metal ions, discrimination between steroids that vary in structure by only a single π bond is possible. The sensing occurs through a triggered aggregation mechanism, which can be mediated by both the presence of metal ions and the steroids. The use of both “turn-on” and “turn-off” fluorophores is essential for good discrimination. As low as 10 μm steroid can be detected, and the discrimination is selective in steroid samples spiked into human urine.     

Self-Assembly of DNA–Peptide Supermolecules: Coiled-Coil Peptide Structures Templated by d-DNA and l-DNA Triplexes Exhibit Chirality-Independent but Orientation-Dependent Stabilizing Cooperativity

DNA nanostructures have been designed and used in many different applications. However, the use of nucleic acid scaffolds to promote the self-assembly of artificial protein mimics is only starting to emerge. Herein five coiled-coil peptide structures were templated by the hybridization of a d -DNA triplex or its mirror-image counterpart, an l -DNA triplex. The self-assembly of the desired trimeric structures in solution was confirmed by gel electrophoresis and small-angle X-ray scattering, and the stabilizing synergy between the two domains was found to be chirality-independent but orientation-dependent. This is the first example of using a nucleic acid scaffold of l -DNA to template the formation of artificial protein mimics. The results may advance the emerging POC-based nanotechnology field by adding two extra dimensions, that is, chirality and polarity, to provide innovative molecular tools for rational design and bottom-up construction of artificial protein mimics, programmable materials and responsive nanodevices.