Integrated zwitterionic conjugated poly(carboxybetaine thiophene) as a new biomaterial platform

An integrated zwitterionic conjugated polymer-based biomaterial platform was designed and studied to address some of the key challenges of conjugated polymers in biomedical applications. This biomaterial platform consists of conjugated polymer backbones and multifunctional zwitterionic side chains. Zwitterionic materials gain electrical conductivity and interesting optical properties through conjugated polymer backbones, and non-biocompatible conjugated polymers obtain excellent antifouling properties, enhanced electrical conductivity, functional groups of bioconjugation and response to environmental stimuli via multifunctional zwitterionic side chains. This platform can potentially be adapted to a wide range of applications (e.g. bioelectronics, tissue engineering and biofuel cell), which require high performance conducting materials with excellent antifouling/biocompatibility at biointerfaces.     

Activating peptides for cellular uptake via polymerization into high density brushes

The utility of peptide therapeutics is thwarted by an inability to enter cells, preventing access to crucial intracellular targets. Herein, we describe a simple and potentially widely applicable solution involving the polymerization of a minimally modified amino acid sequence into a high density brush polymer. Specifically, non-cell penetrating peptides can be rendered competent for cell entry by first including a single Arg or Lys in their amino acid sequence, if one is not already present, along with a norbornenyl unit. This modified monomer is then polymerized by ring opening metathesis polymerization (ROMP). To demonstrate the utility of this strategy, a known therapeutic peptide, which does not penetrate cells on its own, was polymerized. The resulting polymer proficiently entered cells while maintaining its intracellular function. We anticipate that this methodology will find broad use in medicine, increasing or enabling the in vivo efficacy of promising peptide therapeutics.     

Expanding discriminative dimensions for analysis and imaging

Eliminating the contribution of interfering compounds is a key step in chemical analysis. In complex media, one possible approach is to perform a preliminary separation. However purification is often demanding, long, and costly; it may also considerably alter the properties of interacting components of the mixture (e.g. in a living cell). Hence there is a strong interest for developing separation-free non-invasive analytical protocols. Using photoswitchable probes as labelling and titration contrast agents, we demonstrate that the association of a modulated monochromatic light excitation with a kinetic filtering of the overall observable is much more attractive than constant excitation to read-out the contribution from a target probe under adverse conditions. An extensive theoretical framework enabled us to optimize the out-of-phase concentration first-order response of a photoswitchable probe to modulated illumination by appropriately matching the average light intensity and the radial frequency of the light modulation to the probe dynamics. Thus, we can selectively and quantitatively extract from an overall signal the contribution from a target photoswitchable probe within a mixture of species, photoswitchable or not. This simple titration strategy is more specifically developed in the context of fluorescence imaging, which offers promising perspectives.     

Diaryldichalcogenide radical cations

One-electron oxidation of two series of diaryldichalcogenides (C₆F₅E)₂ (13a–c) and (2,6-Mes₂C₆H₃E)₂ (16a–c) was studied (E = S, Se, Te). The reaction of 13a and 13b with AsF₅ and SbF₅ gave rise to the formation of thermally unstable radical cations [(C₆F₅S)₂]˙⁺ (14a) and [(C₆F₅Se)₂]˙⁺ (14b) that were isolated as [Sb₂F₁₁]^– and [As₂F₁₁]^– salts, respectively. The reaction of 13c with AsF₅ afforded only the product of a Te–C bond cleavage, namely the previously known dication [Te₄]²⁺ that was isolated as [AsF₆]^– salt. The reaction of (2,6-Mes₂C₆H₃E)₂ (16a–c) with [NO][SbF₆] provided the corresponding radical cations [(2,6-Mes₂C₆H₃E)₂]˙⁺ (17a–c; E = S, Se, Te) in the form of thermally stable [SbF₆]^– salts in nearly quantitative yields. The electronic and structural properties of these radical cations were probed by X-ray diffraction analysis, EPR spectroscopy, and density functional theory calculations and other methods.     

Azasugar inhibitors as pharmacological chaperones for Krabbe disease

Krabbe disease is a devastating neurodegenerative disorder characterized by rapid demyelination of nerve fibers. This disease is caused by defects in the lysosomal enzyme β-galactocerebrosidase (GALC), which hydrolyzes the terminal galactose from glycosphingolipids. These lipids are essential components of eukaryotic cell membranes: substrates of GALC include galactocerebroside, the primary lipid component of myelin, and psychosine, a cytotoxic metabolite. Mutations of GALC that cause misfolding of the protein may be responsive to pharmacological chaperone therapy (PCT), whereby small molecules are used to stabilize these mutant proteins, thus correcting trafficking defects and increasing residual catabolic activity in cells. Here we describe a new approach for the synthesis of galacto-configured azasugars and the characterization of their interaction with GALC using biophysical, biochemical and crystallographic methods. We identify that the global stabilization of GALC conferred by azasugar derivatives, measured by fluorescence-based thermal shift assays, is directly related to their binding affinity, measured by enzyme inhibition. X-ray crystal structures of these molecules bound in the GALC active site reveal which residues participate in stabilizing interactions, show how potency is achieved and illustrate the penalties of aza/iminosugar ring distortion. The structure–activity relationships described here identify the key physical properties required of pharmacological chaperones for Krabbe disease and highlight the potential of azasugars as stabilizing agents for future enzyme replacement therapies. This work lays the foundation for new drug-based treatments of Krabbe disease.     

Synthesis of poly(10-undecene-1-ol) by metallocene-catalyzed polymerization

Poly(10-undecene-1-ol)s as precursors for potential polar macromonomers were synthesized by metallocene-catalyzed polymerization. For the use as macromonomers, polymerizable terminal double bonds are an important requirement and thus, the investigation of the end groups in the polymers was the main focus of this study. The influence of the catalyst and polymerization conditions on the chain length of the polymer backbone, the monomer conversion as well as the end group characteristics were analyzed. It was possible to find conditions for preparing poly(10-undecene-1-ol)s with terminal double bonds using the catalyst system Cp₂ZrCl₂/MAO. Two other chosen catalysts produced mainly internal double bonds. The poly(10-undecene-1-ol)s could be prepared as atactic or isotactic-rich materials depending on the catalyst used.     

A macrocycle-assisted nanoparticlization process for bulk Ag2S

We report herein a new nanoparticlization process for the bulk-to-nano transformation of Ag₂S by incorporating both top-down and bottom-up approaches. Bulk Ag₂S was dissolved in solution with the assistance of a macrocyclic ligand, hexamethylazacalix[6]pyridine (Py[6]), to produce polynuclear silver sulfide cluster aggregates. All Ag–S cluster aggregates obtained in three crystalline complexes were protected by Py[6] macrocycles. Removing the protective Py[6] macrocycles by protonation led to the generation of unconventional Ag–S nanoparticles with a large energy gap. Theoretical calculations by a hybrid DFT method demonstrated that the silver sulfide clusters with high Ag/S ratio exhibited more localized HOMO–LUMO orbitals, which consequently enlarged their band gap energies. These experimental and theoretical studies broaden our understanding of the fabrication of nanomaterials by virtue of the advantages of both bottom-up and top-down methods and meanwhile provide a viable means of adjusting the band gap of binary nanomaterials independent of their size.     

A hexanuclear gold carbonyl cluster

The hexanuclear gold carbonyl cluster [PPh₄]₂[Au₆(CF₃)₆Br₂(CO)₂] (4) has been obtained by spontaneous self-assembly of the following independent units: CF₃AuCO (1) and [PPh₄][Br(AuCF₃)₂] (3). The cyclo-Au₆ aggregate 4, in which the components are held together by unassisted, fairly strong aurophilic interactions (Au···Au ∼310 pm), exhibits a cyclohexane-like arrangement with chair conformation. These aurophilic interactions also result in significant ν(CO) lowering: from 2194 cm^–1 in the separate component 1 to 2171 cm^–1 in the mixed aggregate 4. Procedures to prepare the single-bridged dinuclear component 3 as well as the mononuclear derivative [PPh₄][CF₃AuBr] (2) are also reported.     

Thermodynamics and kinetics of DNA nanotube polymerization from single-filament measurements

DNA nanotubes provide a programmable architecture for molecular self-assembly and can serve as model systems for one-dimensional biomolecular assemblies. While a variety of DNA nanotubes have been synthesized and employed as models for natural biopolymers, an extensive investigation of DNA nanotube kinetics and thermodynamics has been lacking. Using total internal reflection microscopy, DNA nanotube polymerization was monitored in real time at the single filament level over a wide range of free monomer concentrations and temperatures. The measured polymerization rates were subjected to a global nonlinear fit based on polymerization theory in order to simultaneously extract kinetic and thermodynamic parameters. For the DNA nanotubes used in this study, the association rate constant is (5.99 ± 0.15) × 10⁵ M^–1 s^–1, the enthalpy is 87.9 ± 2.0 kcal mol^–1, and the entropy is 0.252 ± 0.006 kcal mol^–1 K^–1. The qualitative and quantitative similarities between the kinetics of DNA nanotubes, actin filaments, and microtubules polymerization highlight the prospect of building complex dynamic systems from DNA molecules inspired by biological architecture.     

Conducting polyfurans by electropolymerization of oligofurans

Polyfurans have never been established as useful conjugated polymers, as previously they were considered to be inherently unstable and poorly conductive. Here, we show the preparation of stable and conducting polyfuran films by electropolymerization of a series of oligofurans of different chain lengths substituted with alkyl groups. The polyfuran films show good conductivity in the order of 1 S cm^–1, good environmental and electrochemical stabilities, very smooth morphologies (roughness 1–5 nm), long effective conjugation lengths, well-defined spectroelectrochemistry and electro-optical switching (in the Vis-NIR region), and have optical band-gaps in the range of 2.2–2.3 eV. A low oxidation potential needed for polymerization of oligofurans (compared to furan) is a key factor in achievement of improved properties of polyfurans reported in this work. DFT calculations and experiments show that polyfurans are much more rigid than polythiophenes, and alkyl substitution does not disturb backbone planarity and conjugation. The obtained properties of polyfuran films are similar or superior to the properties of electrochemically prepared poly(oligothiophene)s under similar conditions.     

Continuous flow synthesis of poly(methyl methacrylate) via a light‐mediated controlled radical polymerization

Controlled radical polymerizations have significantly impacted the field of polymer science by facilitating the synthesis of polymers with greater control over molecular weight, structure, and dispersity (Ð). As these synthetic techniques continue to evolve, more degrees of control can be realized via external regulation. Recent work has demonstrated external regulation of a controlled radical polymerization process with light using a photoredox Ir‐catalyst. While light offers many advantages as a stimulus for polymerization, scaling up presents unique challenges such as shallow and uneven penetration of light through the reaction medium, which negatively impacts the rate of polymerization. This work addresses some of the challenges associated with scaling up light‐mediated controlled radical polymerizations by employing a continuous flow microreactor and selecting appropriate reactor materials for oxygen sensitive reactions. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 2693–2698     

Synthesis of poly(chloromethylstyrene‐b‐styrene) block copolymers by controlled free‐radical polymerization

The controlled free‐radical polymerization of styrene and chloromethylstyrene monomers in the presence of 2,2,6,6‐tetramethyl‐1‐piperidinyloxyl (TEMPO) has been studied with the aim of synthesizing block copolymers with well‐defined structures. First, TEMPO‐capped poly(chloromethylstyrene) was prepared. Among several initiating systems [self‐initiation, dicumyl peroxide, and 2,2′‐azobis(isobutyronitrile)], the last offered the best compromise for obtaining a good control of the polymerization and a fast polymerization rate. The rate of the TEMPO‐mediated polymerization of chloromethylstyrene was independent of the initial concentration of TEMPO but unexpectedly higher than the rate of the thermal self‐initiated polymerization of chloromethylstyrene. Transfer reactions to the chloromethyl groups were thought to play an important role in the polymerization kinetics and the polydispersity index of the resulting poly(chloromethylstyrene). Second, this first block was used as a macroinitiator in the polymerization of styrene to obtain the desired poly(chloromethylstyrene‐b‐styrene) block copolymer. The kinetic modeling of the block copolymerization was in good agreement with experimental data. The block copolymers obtained in this work exhibited a low polydispersity index (weight‐average molecular weight/number‐average molecular weight < 1.5) and could be chemically modified with nucleophilic substitution reactions on the benzylic site, opening the way to a great variety of architectures. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 3845–3854, 2000     

Mild-temperature Mn2(CO)10-photomediated controlled radical polymerization of vinylidene fluoride and synthesis of well-defined poly(vinylidene fluoride) block copolymers

By contrast to typical high-temperature (100-250 °C) telo-/polymerizations of gaseous fluorinated monomers, carried out in high-pressure metal reactors, the visible light, Mn(2)(CO)(10)-photomediated initiation of vinylidene fluoride (bp = -83 °C) polymerization occurs readily from a variety of alkyl, semifluorinated, and perfluorinated halides at 40 °C, in low-pressure glass tubes and in a variety of solvents, including water and alkyl carbonates. Perfluorinated alkyl iodide initiators also induce a controlled radical polymerization via iodine degenerative transfer (IDT). While IDT proceeds with accumulation of the less reactive P(m)-CF(2)-CH(2)-I vs the P(n)-CH(2)-CF(2)-I chain ends, Mn(2)(CO)(10) enables their subsequent quantitative activation toward the synthesis of well-defined poly(vinylidene fluoride) block copolymers with a variety of other monomers.     

Synthesis and characterization of piperazine-substituted dihydrofuran derivatives viaMn(OAc) 3 mediated radical cyclizations

The aim of this study is to synthesize novel piperazine-containing dihydrofuran compounds (3a-n)from radical additions and cyclizations of diacyl and alkyl-acyl piperazine derivatives (1a-h) with 1,3-dicarbonyl compounds (2a-c) mediated by Mn(OAc) ₃ for the first time. From the reactions of 1a-c with dimedone (2a);1a, 1c, and 1d with acetylacetone (2b); and 1a with ethylacetoacetate(2c) ,the dihydrofuran-piperazine compounds 3a-c, 3d-f, and 3g were obtained in medium to high yields (31%–81%), respectively. In addition, dihydrofuran-piperazine compounds 3h-j and 3k-n were prepared at low to medium yields (20%–40%) from the reactions of 1e-g with 2a and 1e-h with 2c , respectively.     

Addition of aluminium,zinc and magnesium hydrides to rhodium(iii)

We report the addition of M–H bonds (M = Al, Zn, Mg) to a Rh(iii) intermediate generated from the reductive elimination of triethylsilane from [Cp*Rh(H)₂(SiEt₃)₂]. A series of new heterobimetallic complexes possessing Rh–M bonds have been isolated and characterised by a number of spectroscopic (¹H, ²⁹Si, ¹³C, ¹⁰³Rh NMR, infrared, and X-ray diffraction) and computational techniques (NBO and QTAIM analysis). Experimental and computational data are consistent with cleavage of the M–H bond upon addition to rhodium with formation of new Rh–M and Rh–H bonds. Upon photolysis the Al analogue of this series undergoes a further elimination reaction producing triethylsilane and a highly unusual Rh₂Al₂H₄ containing cluster proposed to contain an Al(i) bridging ligand.     

Surface‐initiated polymerization from poly(ethylene terephthalate)

The free‐radical polymerization of styrene initiated from a functionalized poly(ethylene terephthalate) (PET) surface yielded a tethered polymer layer. The anchoring of the initiator species on the PET surface was performed from surface‐reactive groups easily generated by an alkaline hydrolysis of PET. After each surface modification, PET films were characterized by X‐ray photoelectron spectroscopy, measurements of water contact angles, and time‐of‐flight secondary‐ion mass spectrometry. The influence of the polymerization duration, the grafted initiator density, and the grafting mode on the efficiency of the surface‐initiated polymerization of styrene was investigated. In some cases, the tethering of the polystyrene layer on PET could be a reversible process. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 1347–1359, 2003     

Towards more controlled poly(n-butyl methacrylate) by atom transfer radical polymerization

The homogeneous controlled/‘living’ free radical polymerization of n-butyl methacrylate in toluene or o-xylene at 90 °C, in bulk and in solution, using the novel combination of the catalyst bis-triphenylphosphine iron(II)chloride tetrahydrate (FeCl₂ · 4H₂O(PPh₃)₂) with ethyl 2-bromoisobutyrate ((CH₃)₂CBrCO₂Et)) and α,α-dichloroacetophenone (CHCl₂COPh) as initiators has been investigated. The rate of polymerization initiated by the two initiators exhibited first-order kinetic with respect to the monomer. A linear increase of the number-average molecular weight (M_n) versus monomer conversion was observed for these systems. Among the two initiation systems, ethyl 2-bromoisobutyrate gave the fastest polymerization rate. A system with Fe³⁺ added at the beginning of the polymerization was examined and the lowest polydispersity (M_w/M_n∼1.2) was found when 10% Fe³⁺, relative to Fe²⁺ was added.     

Biosynthetic insights provided by unusual sesterterpenes from the medicinal herb Aletris farinosa

A series of novel sesterterpenes (2–6) have been isolated from the roots of Aletris farinosa and structurally characterized by MS, NMR, and X-ray crystallography in conjunction with computational modeling. Their structures provide new insights into the mechanisms of sesterterpene biosynthesis. Specifically, we propose with support from density functional theory computations that the configuration at a single stereocenter determines the fate of a key tetracyclic carbocationic intermediate, derived from an oxidogeranylfarnesol precursor. Whereas one epimer of the carbocation undergoes H⁺ elimination to give 6, the other undergoes a spectacular cascade of seven 1,2-methyl and hydride migrations leading to the previously unreported carbon skeleton of 5. Theoretical calculations suggest that the cascade is triggered by substrate preorganization in the enzyme active site.