Dextran Macroinitiator for Synthesis of Polysaccharide-b-Polypeptide Block Copolymers via NCA Ring-Opening Polymerization.

Synthesis of polysaccharide-b-polypeptide block copolymers represents an attractive goal because of their promising potential in delivery applications. Inspired by recent breakthroughs in N-carboxyanhydride (NCA) ring-opening polymerization (ROP), we present an efficient approach for preparation of a dextran-based macroinitiator and the subsequent synthesis of dextran-b-polypeptides via NCA ROP. This is an original approach to creating and employing a native polysaccharide macroinitiator for block copolymer synthesis. In this strategy, regioselective (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) oxidation of the sole primary alcohol located at the C-6 position of the monosaccharide at the nonreducing end of linear dextran results in a carboxylic acid. This motif is then transformed into a tetraalkylammonium carboxylate, thereby generating the dextran macroinitiator. This macroinitiator initiates a wide range of NCA monomers and produces dextran-b-polypeptides with a degree of polymerization (DP) of the polypeptide up to 70 in a controlled manner (D < 1.3). This strategy offers several distinct advantages, including preservation of the original dextran backbone structure, relatively rapid polymerization, and moisture tolerance. The dextran-b-polypeptides exhibit interesting self-assembly behavior. Their nanostructures have been investigated by dynamic light scattering (DLS) and transmission electron microscopy (TEM), and adjustment of the structure of block copolymers allows self-assembly of spherical micelles and worm-like micelles with varied diameters and aspect ratios, revealing a range of diameters from 60 to 160 nm. Moreover, these nanostructures exhibit diverse morphologies, including spherical micelles and worm-like micelles, enabling delivery applications.

Toward Synthetic Intrinsically Disordered Polypeptides (IDPs): Controlled Incorporation of Glycine in the Ring-Opening Polymerization of N-Carboxyanhydrides.

Intrinsically disordered proteins (IDPs) do not have a well-defined folded structure but instead behave as extended polymer chains in solution. Many IDPs are rich in glycine residues, which create steric barriers to secondary structuring and protein folding. Inspired by this feature, we have studied how the introduction of glycine residues influences the secondary structure of a model polypeptide, poly(l-glutamic acid), a helical polymer. For this purpose, we carried out ring-opening copolymerization with γ-benzyl-l-glutamate and glycine N-carboxyanhydride (NCA) monomers. We aimed to control the glycine distribution within PBLG by adjusting the reactivity ratios of the two NCAs using different reaction conditions (temperature, solvent). The relationship between those conditions, the monomer distributions, and the secondary structure enabled the design of intrinsically disordered polypeptides when a highly gradient microstructure was achieved in DMSO.

A pentameric TRPV3 channel with a dilated pore.

Transient receptor potential (TRP) channels are a large, eukaryotic ion channel superfamily that control diverse physiological functions, and therefore are attractive drug targets1-5. More than 210 structures from more than 20 different TRP channels have been determined, and all are tetramers4. Despite this wealth of structures, many aspects concerning TRPV channels remain poorly understood, including the pore-dilation phenomenon, whereby prolonged activation leads to increased conductance, permeability to large ions and loss of rectification6,7. Here, we used high-speed atomic force microscopy (HS-AFM) to analyse membrane-embedded TRPV3 at the single-molecule level and discovered a pentameric state. HS-AFM dynamic imaging revealed transience and reversibility of the pentamer in dynamic equilibrium with the canonical tetramer through membrane diffusive protomer exchange. The pentamer population increased upon diphenylboronic anhydride (DPBA) addition, an agonist that has been shown to induce TRPV3 pore dilation. On the basis of these findings, we designed a protein production and data analysis pipeline that resulted in a cryogenic-electron microscopy structure of the TRPV3 pentamer, showing an enlarged pore compared to the tetramer. The slow kinetics to enter and exit the pentameric state, the increased pentamer formation upon DPBA addition and the enlarged pore indicate that the pentamer represents the structural correlate of pore dilation. We thus show membrane diffusive protomer exchange as an additional mechanism for structural changes and conformational variability. Overall, we provide structural evidence for a non-canonical pentameric TRP-channel assembly, laying the foundation for new directions in TRP channel research.

Precision Synthesis of Polypeptides via Living Anionic Ring-Opening Polymerization of N-Carboxyanhydrides by Tri-thiourea Catalysts.

The chemistry of α-amino acid N-carboxyanhydrides (NCAs) has a history of over 100 years, but precise and efficient ring-opening polymerization methods for NCAs remain highly needed to facilitate the studies of polypeptides─that is, mimics of natural proteins─in various disciplines. Moreover, the universally accepted NCA polymerization mechanisms are largely limited to the "amine" and the "activated monomer" mechanisms, and the anionic ring-opening polymerization of NCAs has so far not been invoked. Herein, we show an unprecedented anion-binding catalytic system combining tripodal tri-thiourea with sodium thiophenolate that enables the fast and selective anionic ring-opening polymerization of NCAs. This method leads to the precision construction of various polypeptides with living polymerization behavior and is evidenced by narrow molecular weight distributions (Mw/Mn < 1.2), chain extension experiments, and minimal "activated monomer" pathway. Calculations and experimental results elucidate a living anionic polymerization mechanism, and high selectivities for monomer propagation relative to other deleterious side reactions, such as the "activated monomer" pathway, are attributed to the enhanced stabilization of the propagating carbamate anion, which is enforced by an intramolecular hydrogen bond within the tri-thiourea structure.

The Use of Aryl-Substituted Homophthalic Anhydrides in the Castagnoli-Cushman Reaction Provides Access to Novel Tetrahydroisoquinolone Carboxylic Acid Bearing an All-Carbon Quaternary Stereogenic Center.

Novel aryl-substituted homophthalic acids were cyclodehydrated to the respective homophthalic anhydrides for use in the Castagnoli-Cushman reaction. With a range of imines, this reaction proceeded smoothly and delivered hitherto undescribed 4-aryl-substituted tetrahydroisoquinolonic acids with remarkable diastereoselectivity, good yields and no need for chromatographic purification. These findings significantly extend the range of cyclic anhydrides employable in the Castagnoli-Cushman reaction and signify access to a novel substitution pattern around the medicinally relevant tetrahydroisoquinolonic acid scaffold.

New reagent space and new scope for the Castagnoli-Cushman reaction of oximes and 3-arylglutaconic anhydrides.

The Castagnoli-Cushman reaction of oximes, discovered originally for homophthalic anhydride, stimulated the search for other cyclic anhydrides that would be workable in that reaction. Finally, 3-arylglutaconic acid anhydrides were identified as displaying the right reactivity towards a wide range of oximes (including those which did not react with homophthalic anhydride, such as derivatives of aliphatic aldehydes or ketones and substrates with nucleophilic side groups) and delivering, after 18 h at 110 °C in DMSO, ß,γ-unsaturated N-hydroxylactam products lacking the carboxylic acid functionality as the result of decarboxylation accompanying the cyclocondensation process. The reaction was found to be scalable to gram quantities of the starting anhydrides. The products were shown to be easily amenable to post-condensational double-bond transposition or reduction. As expected from cyclic hydroxamic acids, the reaction products were shown to bind Fe(III) and Cu(II) ions (selectively out of a panel of 16 metal cations) and potentially serve as fluorescent metal sensors.

Molecular Design, Preparation, and Characterization of Fluoro-Containing Polyimide Ultrafine Fibrous Membranes with High Whiteness, High Thermal Stability, and Good Hydrophobicity.

Polymeric ultrafine fibrous membranes (UFMs) with high thermal stability and high whiteness are highly desired in modern optoelectronic applications. A series of fluoro-containing polyimide (FPI) UFMs with high whiteness, good thermal stability, and good hydrophobicity were prepared via a one-step electrospinning procedure from the organo-soluble FPI resins derived from a fluoro-containing dianhydride, 4,4'-(hexafluoroisopropylidene) diphthalic anhydride (6FDA), and various diamines containing either pendant trifluoromethyl (-CF3) groups or alicyclic units in the side chains. The obtained FPI UFMs, including FPI-1 from 6FDA and 3,5-diaminobenzotrifluoride (TFMDA), FPI-2 from 6FDA and 2'-trifluoromethyl-3,4'-oxydianiline (3FODA), FPI-3 from 6FDA and 1,4-bis[(4-amino-2-trifluoromethyl)phenoxy]benzene (6FAPB), FPI-4 from 4,4'-bis[(4-amino-2-trifluoromethyl)phenoxy]biphenyl (6FBAB), and FPI-5 from 6FDA and 4'-tert-butyl-cyclohexyl-3,5-diaminobenzoate (DABC) showed whiteness indices (WI) higher than 87.00 and optical reflectance values higher than 80% at the wavelength of 457 nm (R457), respectively. The FPI-5 UFM, especially, showed the highest WI of 92.88. Meanwhile, the prepared PI UFMs exhibited good hydrophobic features with water contact angles (WCA) higher than 105°. At last, the PI UFMs exhibited good thermal stability with glass transition temperatures (Tg) higher than 255 °C, and the 5% weight-loss temperatures (T5%) higher than 510 °C in nitrogen.

Synthesis of Carbonyl-Containing Oxindoles via Ni-Catalyzed Reductive Aryl-Acylation and Aryl-Esterification of Alkenes.

Carbonyl-containing oxindoles are ubiquitous core structures present in many biologically active natural products and pharmaceutical molecules. Nickel-catalyzed reductive aryl-acylation of alkenes using aryl anhydrides or alkanoyl chlorides as acyl sources is developed, providing 3,3-disubstituted oxindoles bearing ketone functionality at the 3-position. Moreover, nickel-catalyzed reductive aryl-esterification of alkenes using chloroformate as ester sources is further developed, affording 3,3-disubstituted oxindoles bearing ester functionality at the 3-position. This strategy has the advantages of good yields and high functional group compatibility.

Preparation of macroporous rigid agarose microspheres by pre-crosslinking with cyclic anhydride.

In this study, a new method for preparing macroporous rigid agarose microspheres was developed by one-step pre-crosslinking method with cyclic anhydride. Three different cyclic anhydrides, namely, maleic anhydride, succinic anhydride, and glutaric anhydride, were used to pre-crosslink agarose. The reaction temperature and the amount of cyclic anhydride in the pre-crosslinking process were optimized to endow agarose with stronger cross-linking. Under the optimal cross-linking condition, macroporous rigid agarose microspheres with homogeneous particle size were successfully obtained by adjusting emulsification method. Cryo-scanning electron microscopy was used to characterize the morphology of cross-linked agarose gel and microspheres. The addition of cyclic anhydride increased the gel aperture of cross-linked agarose microspheres, thereby making the macropores in the microspheres more dense and enhancing the mass transfer in the particles. Under low pressure, the cross-linked agarose microsphere column can effectively separate model proteins at linear flow rates three times higher than the agarose microsphere column. These results indicate that the developed agarose microspheres are a promising high-speed chromatographic medium.

Aliphatic Polyesters with White-Light Clusteroluminescence.

Single-molecule white-light emission (SMWLE) has many advantages in practical applications; however, the fabrication of SMWLE from nonconjugated luminescent polymers, namely, clusteroluminogens (CLgens), is still a big challenge. Herein, the first example of linear nonconjugated polyesters with SMWLE is reported. Twenty-four kinds of nonconjugated aliphatic polyesters with tunable clusteroluminescence (CL) colors and efficiency were synthesized by the copolymerization of six epoxides and four anhydrides. Experimental and calculation results prove that, at the primary structure level, the balance of structural flexibility and rigidity via adjusting the side-chain length significantly enhances the efficiency of CL without wavelength change. However, altering the chemical structures of the monomer from succinic anhydride to trans-maleic anhydride (MA), cis-MA, and citraconic anhydride (CA), secondary structures of these polyesters change from helix to straight and folding sheet accompanied by gradually red-shifted CL from 460 to 570 nm due to the increase in through-space n-π* interactions, as demonstrated by the computational and experimental results. Then, pure SMWLE with CIE coordination (0.30, 0.32) based on overlapped short-wavelength and long-wavelength CL is achieved in CA-based polyesters. This work not only provides further insights into the emission mechanism of CL but also provides a new strategy to manipulate the properties of CL by regulating the hierarchical structures of CLgens.

Catalytic, asymmetric azidations at carbonyls: achiral and meso-anhydride desymmetrisation affords enantioenriched γ-lactams.

An unprecedented organocatalytic process involving the asymmetric addition of azide to meso-anhydrides has been developed, promoted by novel sulfamide-substituted Cinchona alkaloid-based catalysts. Readily available glutaric anhydrides can be smoothly converted to enantioenriched hemi-acyl azides and from there to either γ-amino acids or γ-lactams.

Poly(ester-anhydrides) Derived from Esters of Hydroxy Acid and Cyclic Anhydrides.

The alternating architecture and hydrophobic side chains hinder hydrolytic cleavage and anhydride interchange in poly(sebacic acid-ricinoleic acid) (P(SA-RA)), which provides stable polyanhydrides at room temperature. In this report, a series of polyanhydrides were designed to investigate the effect of ester bonds, hydrophobic side chains, phenyl moieties, and their distance from anhydride bonds on their stability and properties. Polyanhydrides with alternating architecture are constructed by the polymerization of ester-diacids prepared from ricinoleic or other hydroxy acids with anhydrides such as succinic, maleic, and phthalic anhydrides. The hydrophobic side chains are designed closer to anhydride bonds to investigate hindrance to hydrolytic cleavage and anhydride interchange. Polyanhydrides were obtained by the activation of ester-diacid using acetic anhydride followed by melt condensation. The reactions were monitored by NMR, Fourier transform infrared (FTIR), and gel permeation chromatography (GPC). The synthesized poly(ester-anhydride)s with a shorter chain length compared to P(SA-RA) were stable at room temperature. The hydrolytic degradation studies reveal that the phenyl moiety present in poly(ricinoleic acid phthalate) (PRAP) and poly(hydroxystearic acid phthalate) (PHSAP) reduces the hydrolysis of anhydride bonds. Poly(hydroxyoctanoic acid succinate) (PHOAS) demonstrates the highest molecular weight of all tested polymers. The results reveal that the presence of hydrophobic side chains, phenyl moieties, and their distance from anhydride bonds significantly improves the stability. These stable polyanhydrides can provide convenience to use in control drug-delivery applications. The in vitro drug release study using ibuprofen shows that polymers with aromatic units such as PRAP and PHSAP establish sustained release, which presents more than 50 and 40% of ibuprofen over a period of 28 days.

Optically active polyimides with different thermal histories of their preparation.

Optically active linear polyimides and hyperbranched poly (amic acid-imide) were prepared by using procedures varying in particular in the maximum temperature employed in their synthesis. The two types of linear polyimides were based on 4,4'-(hexafluoroisopropylidene)diphthalic anhydride and 1,2-diaminocylohexane enantiomers or 4,4'-(hexafluoroisopropylidene)diphthalic anhydride and 2,2'-diamino-1,1'-binaphthalene enantiomers. The amine-terminated hyperbranched poly (amic acid-imide) was prepared from 4,4'-(hexafluoroisopropylidene)diphthalic anhydride and 4,4',4″-triaminotriphenylmethane, and its end groups were modified with the chiral selectors N-acetyl-D-phenylalanine or N-acetyl-L-phenylalanine. The final structure of the products was analyzed by IR spectroscopy, and their optical activity was evaluated and confirmed by polarimetry or circular dichroism.

Reactivity of 4,5-Dichlorophthalic Anhydride towards Thiosemicarbazide and Amines: Synthesis, Spectroscopic Analysis, and DFT Study.

The cyclic anhydrides are broadly employed in several fields, such as the chemical, plastic, agrochemical, and pharmaceutical industries. This study describes the chemical reactivity of 4,5-dichlorophthalic anhydride towards several nucleophiles, including thiosemicarbazide and different amines, to produce the carboxylic acid derivatives resulting from anhydride's opening, namely, phthalimide and dicarboxylic acid (1-12) products. Their chemical structures are confirmed by NMR, IR and MS spectra analyses. Density-functional theory (DFT) studies are performed using (DFT/B3LYP) with the 6-311G(d, p) basis sets to recognize different chemical and physical features of the target compounds.

Biomimetic Glycosylated Polythreonines by N-Carboxyanhydride Polymerization.

Glycosylated threonine (Thr) is a structural motif found in seemingly disparate natural proteins from deep-sea collagen to mucins. Synthetic mimics of these important proteins are of great interest in biomedicine. Such materials also provide ready access to probe the contributions of individual amino acids to protein structure in a controlled and tunable manner. N-Carboxyanhydride (NCA) polymerization is one major route to such biomimetic polypeptides. However, challenges in the preparation and polymerization of Thr NCAs have impeded obtaining such structures. Here, we present optimized routes to several glycosylated and acetylated Thr NCAs of high analytical purity. Transition metal catalysis produced tunable homo-, statistical, and block-polypeptides with predictable chain lengths and low dispersities. We conducted structural work to examine their aqueous conformations and found that a high content of free OH Thr induces the formation of water-insoluble ß-sheets. However, glycosylation appears to induce a polyproline II-type helical conformation, which sheds light on the role of glyco-Thr in rigid proteins such as mucins and collagen.

A Facile and Unprecedented Route to a Library of Thermostable Formaldehyde-Derived Polyesters: Highly Active and Selective Copolymerization of Cyclic Acetals and Anhydrides.

The development of new strategies for producing polyesters can expand the category of biodegradable materials. Here, we disclose the alternating copolymerization of cyclic acetals (made from formaldehyde and diols) and anhydrides for the first time, using 5 cyclic acetals and 9 anhydrides to afford 45 unprecedented polyesters. At a wide range of reaction temperatures (25 to 140 °C), diverse metal-free Lewis/Brønsted acids are highly active catalysts for these copolymerizations via the cationic mechanism. Of interest, kinetic studies indicate that the copolymerization of cyclic acetals and anhydrides shifts the chemical equilibrium of "cyclic acetals ⇌ polyacetals" to the left, thus yielding polyesters with up to >99 % alternating degree. The obtained polyesters possess high oxygen content ([O] : [C] up to 6 : 7), molecular weights of 2.0-33.3 kDa, narrow polydispersities of 1.2-1.5, low glass transition temperatures (-64 to -27 °C), as well as high decomposition temperatures (275 to 324 °C).

Plasmon-Enhanced Electrochemiluminescence of PTP-Decorated Eu MOF-Based Pt-Tipped Au Bimetallic Nanorods for the Lincomycin Assay.

Plasmonic bimetal nanostructures can be employed to amplify electrochemiluminescence (ECL) signals. In this work, a high-performance ECL platform was constructed using a europium metal-organic framework (MOF) as a luminophore and Au-Pt bimetallic nanorods (NRs) as a plasma source. Due to the SPR effect of Au-Pt NRs, the aptasensor exhibits 2.6-fold ECL intensity compared to that of pure polyaniline (PANI)-decorated perylene tetracarboxylic dianhydride (PTCA)/Eu MOF. Moreover, decoration with PTP greatly enhances the conductivity and stability of Eu MOF, resulting in sizeable plasmon-enhanced electrochemical luminescence. The as-designed plasmon-enhanced ECL aptasensor displayed highly sensitive detection for lincomycin (Lin). The as-proposed aptasensor could quantify Lin from 0.1 mg/mL to 0.1 ng/mL with a limit of detection (LOD) of 0.026 ng/mL.

In situ-formed adhesive hyaluronic acid hydrogel with prolonged amnion-derived conditioned medium release for diabetic wound repair.

Hydrogels have long been used for encapsulating stem cell-derived conditioned mediums to achieve skin regeneration after wounding. However, inappropriate mechanical strength, low adhesion and low elasticity limit their clinical application. To address these challenges, we engineered a hyaluronic acid-based hydrogel grafted with methacrylic anhydride and N-(2-aminoethyl)-4-[4-(hydroxymethyl)-2-methoxy-5-nitrophenoxy]-butanamide (NB) groups to encapsulate a lyophilized amnion-derived conditioned medium (AM-CM). This hydrogel can photopolymerize in situ within 3 s by photo-initiated free-radical crosslinking between methacrylate moieties. Meanwhile, the formed o-nitrosobenzaldehyde groups by photo-irradiation could covalently bond with the amino groups of tissue surface, which allowed strong tissue adhesion. Furthermore, the hydrogel possessed excellent mechanical properties, high elasticity, favorable biocompatibility and prolonged AM-CM release. Our further vitro and in vivo studies showed that the hydrogel significantly accelerated diabetic wound healing by regulating macrophage polarization and promoting angiogenesis. The engineered hydrogel with AM-CM release has high potential to treat chronic wounds in clinics.

Talarodrides A-F, Nonadrides from the Antarctic Sponge-Derived Fungus Talaromyces sp. HDN1820200.

Six new nonadride derivatives, named talarodrides A-F (1-6), were isolated from the Antarctic sponge-derived fungus Talaromyces sp. HDN1820200. All structures including the absolute configurations were deduced by extensive spectroscopic analysis and computational ECD calculations. Compounds 1-4 share a rare caged bicyclo[4.3.1]-deca-1,6-diene with a bridgehead olefin and maleic anhydride core skeleton, while compounds 5 and 6 possess the first case of a naturally occurring 5/7/6 methanocyclonona[c]furan skeleton. Talarodride A (1) and talarodride B (2) showed selective inhibitory effects against Proteus mirabilis and Vibrio parahemolyticus with MICs of 3.13-12.5 µM.

T3P-Promoted Synthesis of a Series of 2-Aryl-3-phenyl-2,3-dihydro-4H-pyrido[3,2-e][1,3]thiazin-4-ones and Their Activity against the Kinetoplastid Parasite Trypanosoma brucei.

A series of fourteen 2-aryl-3-phenyl-2,3-dihydro-4H-pyrido[3,2-e][1,3]thiazin-4-ones was prepared at room temperature by T3P-mediated cyclization of N-phenyl-C-aryl imines with thionicotinic acid, two difficult substrates. The reactions were operationally simple, did not require specialized equipment or anhydrous solvents, could be performed as either two or three component reactions, and gave moderate-good yields as high as 63%. This provides ready access to N-phenyl compounds in this family, which have been generally difficult to prepare. As part of the study, the first crystal structure of neutral thionicotinic acid is also reported, and showed the molecule to be in the form of the thione tautomer. Additionally, the synthesized compounds were tested against T. brucei, the causative agent of Human African Sleeping Sickness. Screening at 50 µM concentration showed that five of the compounds strongly inhibited growth and killed parasites.