Macrocyclic Oligomers Research Articles

Evaluation of the Immunosafety of Cucurbit[n]uril In Vivo.

Cucurbiturils are a family of macrocyclic oligomers capable of forming host-guest complexes with various molecules. Due to noncovalent binding to drug molecules and low toxicity, cucurbiturils has been extensively investigated as potential carriers for drug delivery. However, the immune system's interactions with different drug carriers, including cucurbiturils, are still under investigation. In this study, we focused on cucurbiturils' immunosafety and immunomodulation properties in vivo. We measured blood counts and lymphocyte subpopulations in blood, spleen, and bone marrow, and assessed the in vivo toxicity to spleen and bone marrow cells after intraperitoneal administration to BALB/c mice. When assessing the effect of cucurbit[6]uril on blood parameters after three intraperitoneal injections within a week in laboratory animals, a decrease in white blood cells was found in mice after injections of cucurbit[6]util, but the observed decrease in the number of white blood cells was within the normal range. At the same time, cucurbit[7]uril and cucurbit[8]uril did not affect the leukocyte counts of mice after three injections. Changes in the number of platelets, erythrocytes, and monocytes, as well as in several other indicators, such as hematocrit or erythrocyte volumetric dispersion, were not detected. We show that cucurbiturils do not have immunotoxicity in vivo, with the exception of a cytotoxic effect on spleen cells after сucurbit[7]uril administration at a high dosage. We also evaluated the effect of cucurbiturils on cellular and humoral immune responses. We founded that cucurbiturils in high concentrations affect the immune system in vivo, and the action of various cucurbiturils differs in different homologues, which is apparently associated with different interactions in the internal environment of the body.

Synthesis of a macrocyclic oligomer of pyridylbenzoxazole utilizing dynamic covalent bonds and its unsymmetric conversion.

A new unsymmetric macrocycle was synthesized by an effective and high yield 3-step synthesis, which was composed of macrocyclization, irreversible conversion, and desymmetrization. The dynamic nature of imine bonds as well as selective conversion based on strain release were utilized. Moreover, the unsymmetric macrocycle formed an interesting bivalve-like 2 : 1 complex with zinc.

Stereogenic π-Conjugated Macrocycles: Synthesis, Structure, and Chiroptical Properties Including Circularly Polarized Luminescence

AbstractHighly symmetrical and aesthetically pleasing molecules have attracted the attention of organic chemists. We synthesized new highly symmetric stereogenic π-conjugated macrocycles with planar or axial chirality. Macrocyclic oligomers synthesized by Yamamoto coupling or Suzuki–Miyaura cross-coupling from the π-unit containing chirality. These cyclization reactions gave multiple oligomers in relatively high yields. We then elucidated their structures and investigated their chiroptical properties, including circular dichroism (CD) and circularly polarized luminescence (CPL). Because of the selection rule for rigid and symmetric structures, these macrocycles exhibit a high dissymmetry factor (g abs or g lum) for circularly polarized light in CD or CPL. Several rigid cyclic compounds retain a highly symmetric structure in the excited state and exhibit higher g lum values than common chiral organic compounds. This Account provides a brief background regarding chiroptical properties, followed by a summary of the various macrocycles synthesized in this study. We are glad if this Account will be a source of ideas not only for chemists working with π-conjugated compounds, but also for synthetic chemists working with chiral compounds, especially those engaged in asymmetric synthesis.1 Introduction2 Brief Description of Chiroptical Properties3 Stereogenic Macrocycle Based on [2.2]Paracyclophane3.1 Stereogenic Double-decker Oligothiophene3.2 Stereogenic Biselenophene Macrocycle3.3 Helical Oligophenylene Linked with [2.2]Paracyclophane4 Stereogenic Macrocycle Based on Binaphthyl4.1 Cyclic Oligomer of Chiral Binaphthyl4.2 Doubly Twisted Binaphthyl Dimer4.3 Cyclic Oligomer of Binaphthyl Extended with Paraphenylene4.4 Curved Helical Paraphenylene Anchoring Chiral Binaphthyl4.5 Binaphthyl-Hinged [5]-Helicene5 Summary

Water-Soluble Chiral Cyclic Peptoids and Their Sodium and Gadolinium Complexes: Study of Conformational and Relaxometric Properties.

Cyclic peptoids are macrocyclic oligomers of N-substituted glycines with specific folding abilities and excellent metal binding properties. In this work, we show how strategic positioning of chiral (S)- and (R)-(1-carboxyethyl)glycine units influences the conformational stability of water-soluble macrocyclic peptoids as sodium complexes. The reported results are based on nuclear magnetic resonance spectroscopy, extensive computational studies, and X-ray diffraction analysis using single crystals grown from aqueous solutions. The studies include 1H relaxometric investigations of hexameric cyclic peptoids in the presence of the Gd3+ ion to assess their thermodynamic stabilities and relaxivities.

Synthesis of Degradable Polysulfamides via Sulfur(VI) Fluoride Exchange Click Polymerization of AB-Type Monomers.

Polysulfamides are the -SO2- analogues of polyureas and form an intriguing family of polymers containing hydrogen-bond donor and acceptor groups. However, unlike polyureas, their physical properties are mostly unknown because of the scarcity of synthetic methods to access such polymers. Herein, we report an expedient synthesis of AB monomers for the synthesis of polysulfamides via Sulfur(VI) Fluoride Exchange (SuFEx) click polymerization. Upon optimization of the step-growth process, a variety of polysulfamides were isolated and characterized. The versatility of the SuFEx polymerization allowed structural modulation of the main chain through the incorporation of aliphatic or aromatic amines. While all synthesized polymers presented high thermal stability via thermogravimetric analysis, the glass-transition temperature and crystallinity were shown to be highly tied to the structure of the backbone between repeating sulfamide units through differential scanning calorimetry and powder X-ray diffraction. Careful analysis via matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and X-ray crystallography also revealed the formation of macrocyclic oligomers during the polymerization of one AB monomer. Finally, two protocols were developed to efficiently degrade all synthesized polysulfamides through either chemical recycling for polymers derived from aromatic amines or oxidative upcycling for those based on aliphatic amines.

Native Cyclodextrins as Complexation Agents for Pterostilbene: Complex Preparation and Characterization in Solution and in the Solid State

Pterostilbene (3,5-dimethoxy-4′-hydroxystilbene, PTB) is a natural dietary stilbene, occurring primarily in blueberries and Pterocarpus marsupium heartwood. The interest in this compound is related to its different biological and pharmacological properties, such as its antioxidant, anti-inflammatory, and anticarcinogenic activities and its capacity to reduce and regulate cholesterol and blood sugar levels. Nevertheless, its use in therapy is hindered by its low aqueous solubility; to overcome this limitation we studied the feasibility of the use of cyclodextrins (CDs) as solubility-enhancing agents. CDs are natural macrocyclic oligomers composed of α-d-glucose units linked by α-1,4 glycosidic bonds to form torus-shaped molecules, responsible for inclusion complex formation with organic molecules. In particular, the aim of this study was to evaluate the feasibility of complexation between PTB and native CDs using various preparative methods. The isolated solid products were characterized using differential scanning calorimetry (DSC), simultaneous thermogravimetric/DSC analysis (TGA/DSC), Fourier transform infrared (FT-IR) spectroscopy, and X-ray diffraction (XRD) on powder and single crystals. The results indicated little or no evidence of the affinity of PTB to complex with α-CD using the kneading method. However, with β-CD and γ-CD thermal analysis revealed an interaction which was also corroborated by FT-IR and 1H-NMR spectroscopy. With β-CD, a hydrated complex of PTB was isolated and its characterization by single-crystal XRD revealed, for the first time, the mode of inclusion of the PTB molecule in the cavity of a CD. To complement the solid-state data, liquid-phase studies were carried out to establish the effect of CDs on the aqueous solubility of PTB and to determine the complex stoichiometries and the association constants for complex formation. Phase-solubility studies showed AL-type profiles for α- and β-CD and a BS profile for γ-CD, with K1:1 values of 1144, 4950, and 133 M−1 for α-CD·PTB, β-CD·PTB, and γ-CD·PTB, respectively. The stoichiometry of CD·PTB complexes, determined by Job’s method, revealed for each system a 1:1 molar ratio. The dissolution rate of PTB was approximately doubled just by employing simple physical mixtures, but the best performance was achieved by products obtained via kneading and co-precipitation, which effected the complete dissolution of PTB in 40 and 20 min for β-CD and γ-CD, respectively.

Polyaryletherketone (PAEK) thermoplastic composites via in-situ ring opening polymerisation

This work investigates the synthesis and characterisation of macrocyclic oligomers (MCO) from 4, 4′-difluoro benzophenone and catechol, their ring opening polymerisation, fabrication into carbon fibre reinforced composite materials and depolymerisation. The MCOs are polymerized using Caesium fluoride at a variety of temperatures, times, and catalyst concentrations to produce ortho polyaryletherketone polymers (oPAEK) of varying glass transition temperature (Tg) and molecular weight. A dimer formed during synthesis which does not polymerise is removed enabling a more convenient synthesis using lower temperature and catalyst concentration. The first carbon fibre composite of oPAEK fabricated using in-situ ring opening polymerisation methods is therefore presented with and without MCO dimer. Composites made without dimer formed are able fabricated at 10 °C lower temperature than the corresponding MCO containing dimer and have improved thermal and mechanical properties. Depolymerisation of the MCO and the re-emergence of cyclic structures is reported, highlighting the reversible nature of the chemistry. The results presented here provide important guidance on the future development of in-situ polymerisation of high performance thermoplastic composites.

Demystifying and unravelling the molecular structure of the biopolymer sporopollenin.

We report the unsolved molecular structure of the complex biopolymer sporopollenin exine extracted from Lycopodium clavatum pollen grains. TOF-SIMS and CID-MS/MS, MALDI-TOF-MS and CID-TOF/TOF-MS/MS were used for the analysis of this complex biopolymer sporopollenin exine extracted from Lycopodium clavatum pollen grains. Solid-state 1 H- and 13 C-NMR, 2D 1 H-1 H NOESY, Rotor-synchronized 13 C{1 H} HSQC, and 13 C{1 H} multi CP-MAS NMR experiments were used to confirm the structural assigments revealed by MS and MS/MS studies. Finally, high-resolution XPS was used to check for the presence of aromatic components in sporopollenin. The combined MS and NMR analyses showed that sporopollenin contained poly(hydroxy acid) dendrimer-like networks with glycerol as a core unit, which accounted for the sporopollenin empirical formula. In addition, these analyses showed that the hydroxy acid monomers forming this network contained a β-diketone moiety. Moreover, MALDI-TOF-MS and MS/MS allowed us to identify a unique macrocyclic oligomeric unit composed of polyhydroxylated tetraketide-like monomers. Lastly, high-resolution X-ray photoelectron spectroscopy (HR-XPS) showed the absence of aromaticity in sporopollenin. We report for the first time the two main building units that form the Lycopodium clavatum sporopollenin exine. The first building unit is a macrocyclic oligomer and/or polymer composed of polyhydroxylated tetraketide-like monomeric units, which represents the main rigid backbone of the sporopollenin biopolymer. The second building unit is the poly(hydroxy acid) network in which the hydroxyl end groups can be covalently attached by ether links to the hydroxylated macrocyclic backbone to form the sporopollenin biopolymer, a spherical dendrimer. Such spherical dendrimers are a typical type of microcapsule that have been used for drug delivery applications. Finally, HR-XPS indicated the total absence of aromaticity in the sporopollenin exine.

A modular approach for organizing dimeric coiled coils on peptoid oligomer scaffolds.

We report a general approach to promote the folding of synthetic oligopeptides capable of forming homodimeric coiled coil assemblies. By pre-organizing the peptides on macrocyclic oligomer scaffolds, the stability of the coiled coils is enhanced with an observed increase in the melting temperature of 30 °C to 40 °C. Molecular dynamics simulations substantiate the hypothesis that the enhanced stability is established by constraining motion at the peptide termini and by pre-organizing intramolecular helix-helix contacts. We demonstrate the modularity of this approach by using a family of peptoid scaffolds to promote the folding of a dimeric coiled coil. Importantly, this strategy for templating coiled coils allows preservation of native amino acid sequences. Comparing a macrocyclic peptoid scaffold to its linear counterparts indicates that both types of assemblies are effective for organizing stable coiled coils. These results will guide future designs of coiled coil peptides for biomedical applications and as building blocks for more complex supramolecular assemblies.

On the synthesis of polyphenylene sulfide and copolymers based on it by the reaction of nonequilibrium polycondensation

Polyphenylene sulfide is a semicrystalline engineering thermoplastic, in the world market of superconstructive materials is presented in two modifications: the first is a cross-linked material, the second is a linear polymer with a highly ordered supramolecular structure.Polyphenylene sulfides, synthesized according to the classical procedure in N-methyl-2-pyrrolidone, are characterized by low molecular weight characteristics due to the occurrence of side reactions. The main yield of the target product does not exceed 45%, even with an increase in the synthesis time of up to 120 hours.Polymers with higher viscosity characteristics can be obtained by heat treatment of synthesized polyphenylene sulfide at 240-260 °С. Copolymers with new monomeric fragments, such as sulfonic, ketone, amide, imide, etc., have been synthesized, which lead to amorphous polymers. The copolymers obtained are well soluble at room temperature and have a higher yield and a molecular weight. The introduction of cyclic groups into the macromolecule of polyphenylene sulfide results in an increase in heat resistance (500 °C) and solubility. Over the past 10-15 years, special attention has been paid to the synthesis of macrocyclic oligomers, which are used subsequently for the preparation of high molecular copolymers by a ring-opening polymerization reaction. This technique allows to obtain polymers in a short time and without the formation of by-products.During the synthesis of copolymers, extensive knowledge of the effect of the chemical structure on the performance properties of materials was obtained, and new methods were developed that reduced the possibility of percolation reactions. Thus, the synthesis of new polyheteroarylenes becomes topical, the review reflects the results of research over the past few years on the development on their basis of materials with unique valuable properties.

Macrocyclic oligomers as compatibilizing agent for hemp fibres/biodegradable polyester eco-composites

Ring:chain equilibria (RCE), existing under appropriate reaction conditions, between a linear polyester and the corresponding family of macrocyclic oligomers (MCOs), were exploited to develop an original compatibilizing pathway for preparing eco-composites based on hemp fibres and a biodegradable random co-polyester, namely poly(1,4-butylene adipate-co-terephthalate) (PBAT) with 50:50 adipate:therephthalate proportion.Cyclo-depolymerization (CDP) of PBAT was successfully carried out at high dilution using various solvents, catalysts, and reaction times. The reconversion of MCOs into linear chains by entropically-driven ring-opening polymerization (ED-ROP) occurs by simple heating in the bulk. This reaction, after optimization of catalyst amount, temperature, and reaction time, was used for the surface modification of hemp fibres. PBAT-based eco-composites containing hemp fibres as such or pre-modified by treatment with the MCOs were then prepared and characterized by morphological, mechanical and dynamic-mechanical analysis.

Synthesis of Alkaline Anion Exchange Membranes with Chemically Stable Imidazolium Cations: Unexpected Cross-Linked Macrocycles from Ring-Fused ROMP Monomers

In order to prepare base-stable, mechanically strong, and synthetically feasible alkaline anion exchange membranes (AAEMs) for applications in alkaline fuel cells, an imidazolium-fused cyclooctene monomer was prepared and subjected to ring-opening metathesis polymerization (ROMP) conditions. Surprisingly, macrocyclic oligomers were obtained instead of high molecular weight polymers. High-performance AAEMs were synthesized by using a bifunctional monomer to cross-link the macrocycles. The resultant AAEMs showed high ionic conductivities (σOH– = 59 mS/cm at 50 °C), robust mechanical properties, and excellent alkaline stabilities.

Evidence for Ion-Templation During Macrocyclooligomerization of Depsipeptides.

The ion-mediated Mitsunobu macrocyclooligomerization (M-MCO) reaction of hydroxy acid depsipeptides provides small collections of cyclic depsipeptides with good mass recovery. The approach can produce good yields of a single macrocycle or provide rapid access to multiple oligomeric macrocycles in good overall yield. While Lewis acidic alkali metal salts are known to play a role in the outcome of MCO reactions, it is unclear whether their effect is due to an organizational (e.g., templating) mechanism. Isothermal titration calorimetry (ITC) was used to study macrocycle-metal ion binding interactions, and this report correlates these thermodynamic measurements to the (kinetically determined) size distributions of depsipeptides formed during a Mitsunobu-based macrocyclooligomerization (MCO). Key trends have been identified in quantitative metal ion-cyclic depsipeptide binding affinity ( Ka), enthalpy of binding (Δ H), and stoichiometry of complexation across discrete series of macrocycles, and they provide the first analytical platform to rationally select a metal-ion template for a targeted size regime of cyclic oligomeric depsipeptides.

Disulphide bond exchange inhibited by air - kinetic and thermodynamic products in a library of macrocyclic cysteine derivatives.

In this paper we present the synthesis and reactivity of dithiols comprising of two cysteine moieties attached to a dipicolinic acid core. Oxidation of these thiols provides oligomeric macrocycles. Monomers with 13-membered rings are kinetic products which are, however, strained and readily transform into higher oligomers under basic conditions or elevated temperature via a disulphide exchange reaction. Dimers, which are the most stable thermodynamic products, equilibrate only under inert conditions with thiolate as a catalyst. Under aerobic conditions, the thiols are oxidised before the equilibrium is reached.

Tetraaza[14]- and Octaaza[18]paracyclophane: Synthesis and Characterization of Their Neutral and Cationic States.

Two kinds of aza[1n]paracyclophanes, tetraaza[14]paracyclophane (P4) and octaaza[18]paracyclophane (P8), were synthesized as the smallest and the largest monodisperse macrocyclic oligomers of polyaniline ever made. Herein we report the electronic nature of the cationic species of these two macrocycles with different ring size. By combining ESR spectroscopy and DFT calculations it was suggested that P4·+ was classified as delocalized class III or poised on the class II/III borderline while P8·+ was regarded as a localized class II mixed-valence system. We successfully isolated the dication of P4 as a stable dicationic salt P42+·2[SbF6]-, and the structure of P42+ was determined by X-ray crystal analysis. Variable-temperature NMR measurements for P42+·2[SbF6]- unequivocally showed that P42+ was a 22π electron system with a singlet ground state. The supercharged hexacation of P8 was also isolated as P86+·6[SbCl6]-, and X-ray crystal analysis revealed that P86+ includes one SbCl6- anion in its macrocyclic cavity.

Conformational isomerism in cyclic peptoids and its specification.

Most of the structural studies made on the secondary structure of peptoids describe their geometric attributes in terms of the classic Ramachandran plot (based on the local analysis of ω, ψ, χ, φ dihedral angles). However, little intuitive understanding is available from internal coordinates when stereochemistry is involved. In this contribution we list all the conformationally stable cyclic peptoids reported up to the year 2017 and propose a simple method to define their geometric arrangement in terms of planar chirality. Evidence of conformational isomerism (due to the long average time of single bond rotation) and conformational chirality (induced by the absence of roto-reflection axes) in this promising class of synthetic macrocycles is provided by NMR spectroscopy (using Pirkle's alcohol as chiral solvating agent) and careful evaluation of X-ray crystallographic studies. The full understanding of the oligomeric macrocycles' structural properties and the clear framing of their conformational isomerism in a proper conceptual scheme is fundamental for future application of peptoids in asymmetric synthesis, chiral recognition and supramolecular chemistry.

M-Phenylene-Linked Dipyrrins and Their Boron-Difluoride Complexes as Variously Shaped Macrocyclic Oligomers.

The effectiveness of a m-phenylene linker, which has rigidity as well as rotational flexibility, is presented to produce a series of variously shaped macrocyclic oligomers of dipyrrins and BODIPYs, whose structures were revealed by X-ray crystallography and 1H NMR analysis. Although the chemical structures of the repeating units are the same for dipyrrin/BODIPY oligomers, their absorbance and emission properties changed significantly depending on the size and shape of the macrocycles.

Organometallic chemistry: Fused ferrocenes come full circle.

Chemists have long been fascinated by electron delocalization, from both a fundamental and applied perspective. Macrocyclic oligomers containing fused ferrocenes provide a new structural framework — containing strongly interacting metal centres — that is capable of supporting substantial charge delocalization.

N-Substituted Dicyanomethylphenyl Radicals: Dynamic Covalent Properties and Formation of Stimuli-Responsive Cyclophanes by Self-Assembly.

Dynamic covalent bonds and their chemistry have been of particular interest both from a fundamental and materials science aspect. Demonstrated herein is that triphenylamine (TPA) and carbazole (Cz), substituted with a dicyanomethyl radical, are useful motifs for dynamic covalent chemistry as they have the appropriate bond strength between monomer units as well as high stability and synthetic simplicity. TPA and Cz units substituted by two dicyanomethyl radicals formed macrocyclic oligomers classified as novel types of azacyclophanes, and in particular, the TPA-based diradical gave a cyclic dimer in almost quantitative yield. The cyclic oligomers exhibited thermo- and mechanochromic behavior resulting from the generation of radical species by intermonomer C-C bond cleavage.

N‐Substituted Dicyanomethylphenyl Radicals: Dynamic Covalent Properties and Formation of Stimuli‐Responsive Cyclophanes by Self‐Assembly

AbstractDynamic covalent bonds and their chemistry have been of particular interest both from a fundamental and materials science aspect. Demonstrated herein is that triphenylamine (TPA) and carbazole (Cz), substituted with a dicyanomethyl radical, are useful motifs for dynamic covalent chemistry as they have the appropriate bond strength between monomer units as well as high stability and synthetic simplicity. TPA and Cz units substituted by two dicyanomethyl radicals formed macrocyclic oligomers classified as novel types of azacyclophanes, and in particular, the TPA‐based diradical gave a cyclic dimer in almost quantitative yield. The cyclic oligomers exhibited thermo‐ and mechanochromic behavior resulting from the generation of radical species by intermonomer C−C bond cleavage.