James Gardiner

Emerging rules for effective antimicrobial coatings

In order to colonize abiotic surfaces, bacteria and fungi undergo a profound change in their biology to form biofilms: communities of microbes embedded into a matrix of secreted macromolecules. Despite strict hygiene standards, biofilm-related infections associated with implantable devices remain a common complication in the clinic. Here, the application of highly dosed antibiotics is problematic in that the biofilm (i) provides a protective environment for microbes to evade antibiotics and/or (ii) can provide selective pressure for the evolution of antibiotic-resistant microbes. However, recent research suggests that effective prevention of biofilm formation may be achieved by multifunctional surface coatings that provide both non-adhesive and antimicrobial properties imparted by antimicrobial peptides. Such coatings are the subject of this review.

Synthesis, structure, and biological applications of α-fluorinated β-amino acids and derivatives.

This review gives a broad overview of the state of play with respect to the synthesis, conformational properties, and biological activity of α‐fluorinated β‐amino acids and derivatives. General methods are described for the preparation of monosubstituted α‐fluoro‐β‐amino acids (Scheme 1). Nucleophilic methods for the introduction of fluorine predominantly involve the reaction of DAST with alcohols derived from α‐amino acids, whereas electrophilic sources of fluorine such as NFSI have been used in conjunction with ArndtEistert homologation, conjugate addition or organocatalyzed Mannich reactions. α,α‐Difluoro‐β‐amino acids have also been prepared using DAST; however, this area of synthesis is largely dominated by the use of difluorinated Reformatsky reagents to introduce the difluoro ester functionality (Scheme 9). α‐Fluoro‐β‐amino acids and derivatives analyzed by X‐ray crystal and NMR solution techniques are found to adopt preferred conformations which are thought to result from stereoelectronic effects associated with F located close to amines, amides, and esters (Figs. 2–6). α‐Fluoro amide and β‐fluoro ethylamide/amine effects can influence the secondary structure of α‐fluoro‐β‐amino acid‐containing derivatives including peptides and peptidomimetics (Figs. 7–9). α‐Fluoro‐β‐amino acids are also components of a diverse range of bioactive anticancer (e.g., 5‐fluorouracil), antifungal, and antiinsomnia agents as well as protease inhibitors where such fluorinated analogs have shown increased potency and spectrum of activity.

Fluoropolymers: Origin, Production, and Industrial and Commercial Applications

Fluoropolymers have had a profound effect on all aspects of industry since their discovery during the 1930s. This review briefly describes the historical development of the fluoropolymer industry, with a focus on traditional fluoroplastics, and lists the major industrial and commercial materials currently in use. These include polytetrafluoroethylene (PTFE, Teflon), polychlorotrifluoroethylene (PCTFE), fluorinated ethylene propylene (FEP), the ethylene copolymer of tetrafluoroethylene (ETFE), the ethylene copolymer of chlorotrifluoroethylene (ECTFE), perfluoroalkoxy (PFA), polyvinylfluoride (PVF), polyvinyldifluoride (PVDF), Nafion, fluoroethylenevinylether (FEVE), a semicrystalline three component terpolymer of tetrafluoroethylene, hexafluoropropylene, and vinylidene fluoride (THV), Teflon-AF, Cytop, and Hyflon. The production, processing, and properties of these fluoropolymers are discussed, together with examples of the specific uses in chemical industry, manufacturing, electronics, architecture, energy, health and domestic sectors. Other related fluoropolymers such as fluoroelastomers, perfluoropolyethers, and fluorosurfactants are briefly mentioned. Environmental aspects of fluoropolymers are considered as is the current state of the fluoropolymer industry.

Enantioselective synthesis of alpha-fluorinated beta2-amino acids.

A methodology for the enantioselective synthesis of alpha-fluorinated beta2-amino acids has been developed from readily available carboxylic acids 3. Conversion to the Evans oxazolidinone followed by enantioselective fluorination and alkylation gave 7 in high diastereomeric excess (>95%). Subsequent removal of the oxazolidinone and amination at the Bn-protected hydroxyl center gave optically active alpha-fluorinated beta2-amino acids.

On the Terminal Homologation of Physiologically Active Peptides as a Means of Increasing Stability in Human Serum – Neurotensin, Opiorphin, B27‐KK10 Epitope, NPY

The terminal homologation by CH2 insertion into the peptides mentioned in the title is described. This involves replacement of the N‐terminal amino acid residue by a β2‐ and of the C‐terminal amino acid residue by a β3‐homo‐amino acid moiety (β2hXaa and β3hXaa, resp.; Fig. 1). In this way, the structure of the peptide chain from the N‐terminal to the C‐terminal stereogenic center is identical, and the modified peptide is protected against cleavage by exopeptidases (Figs. 2 and 3). Neurotensin (NT; 1) and its C‐terminal fragment NT(8–13) are ligands of the G‐protein‐coupled receptors (GPCR) NT1, NT2, NT3, and NT analogs are promising tools to be used in cancer diagnostics and therapy. The affinities of homologated NT analogs, 2b–2e, for NT1 and NT2 receptors were determined by using cell homogenates and tumor tissues (Table 1); in the latter experiments, the affinities for the NT1 receptor are more or less the same as those of NT (0.5–1.3 vs. 0.6 nM). At the same time, one of the homologated NT analogs, 2c, survives in human plasma for 7 days at 37° (Fig. 6). An NMR analysis of NT(8–13) (Tables 2 and 4, and Fig. 8) reveals that this N‐terminal NT fragment folds to a turn in CD3OH. – In the case of the human analgesic opiorphin (3a), a pentapeptide, and of the HIV‐derived B27‐KK10 (4a), a decapeptide, terminal homologation (→3b and 4b, resp.) led to a 7‐ and 70‐fold half‐life increase in plasma (Fig. 9). With N‐terminally homologated NPY, 5c, we were not able to determine serum stability; the peptide consisting of 36 amino acid residues is subject to cleavage by endopetidases. Three of the homologated compounds, 2b, 2c, and 5c, were shown to be agonists (Fig. 7 and 11). A comparison of terminal homologation with other stability‐increasing terminal modifications of peptides is performed (Fig. 5), and possible applications of the neurotensin analogs, described herein, are discussed.

2-Nitroveratryl as a Photocleavable Thiol-Protecting Group for Directed Disulfide Bond Formation in the Chemical Synthesis of Insulin

Chemical synthesis of peptides can allow the option of sequential formation of multiple cysteines through exploitation of judiciously chosen regioselective thiol-protecting groups. We report the use of 2-nitroveratryl (oNv) as a new orthogonal group that can be cleaved by photolysis under ambient conditions. In combination with complementary S-pyridinesulfenyl activation, disulfide bonds are formed rapidly in situ. The preparation of Fmoc-Cys(oNv)-OH is described together with its use for the solid-phase synthesis of complex cystine-rich peptides, such as insulin.

Rational design of a hexapeptide hydrogelator for controlled-release drug delivery

The amphiphilic peptide sequence H-Phe-Glu-Phe-Gln-Phe-Lys-OH (MBG-1) is developed as a novel hydrogelator for use in controlled-drug release administration, which is the smallest tunable ionic self-complementary hydrogelating peptide reported to date making it attractive for larger scale preparation. Hydrogelation is demonstrated to result from self-assembly of the peptide into beta-sheet nanofibers that are physically cross-linked by intertwining as well as larger bundle formation. Finally, the release of two small molecule cargos, fluorescein sodium and ciprofloxacin hydrochloride, is demonstrated revealing a two-stage zero-order sustained release profile up to 80% cumulative release over eight days.

Synthesis and X-ray structure of a 1,2,3,6-tetrahydropyridine-based phenylalanine mimetic

Abstract A ring-closing metathesis reaction on methyl (2 R )-( N -allyl- N -benzoylamino)-2-benzylpent-4-enoate 5 , prepared as a single isomer from L-phenylalanine, gave a conformationally restricted 1,2,3,6-tetrahydropyridine-based phenylalanine mimetic 6 in good yield. The solid state conformation of which was determined by X-ray crystallography.

Dithiocarbamate RAFT agents with broad applicability – the 3,5-dimethyl-1H-pyrazole-1-carbodithioates

3,5-Dimethyl-1H-pyrazole-1-carbodithioates are shown to be extremely versatile dithiocarbamate RAFT agents with wide-spread applicability. The cyanomethyl and benzyl dithiocarbamates offer very low dispersities (Đ < 1.1) for polymers based on more activated monomers [MAMs: methyl acrylate (MA), N,N-dimethylacrylamide (DMA) and styrene (St)] and Đ < 1.3 in polymerization of vinyl acetate (VAc), a less activated monomer (LAM). The tertiary, 2-cyano-2-butyl dithiocarbamate, provides molar mass control and Đ < 1.5 in methyl methacrylate (MMA) polymerization. Lower dispersities can be obtained for MMA copolymers. End group fidelity was proved with the synthesis of block copolymers, poly(DMA)-block-poly(MA). With the ability to control polymerization of both MAMs and LAMs, the RAFT agents were also shown to be suitable for the synthesis of a poly(MAM)-block-poly(LAM), specifically poly(DMA)-block-poly(VAc). The RAFT agents are an appropriate replacement for trithiocarbonate RAFT agents in most circumstances and have the distinct advantage that the RAFT agents have low odour and the derived polymers do not develop odour on storage (i.e., no low molar mass thiols are generated).

Injectable peptide hydrogels for controlled-release of opioids

Herein, a family of hydrogel-forming peptides was designed starting from the short, tunable and amphipathic hexapeptide hydrogelator H-Phe-Glu-Phe-Gln-Phe-Lys-OH (1). The hydrophobic side chains as well as the nature of both N- and C-termini were modified in order to obtain suitable gelation conditions and drug release profiles for in vivo application. To potentially increase the enzymatic stability, an all-D analogue was prepared as well. After their macroscopic and microscopic characterization by rheology and transmission electron microscopy (TEM) analysis, opioid drugs were encapsulated into the hydrogels and sustained release experiments were carried out. Hydrogel toxicity was assessed in cell viability assays. Based on the physicochemical, mechanical, and noncytotoxic properties, H-Phe-Glu-Phe-Gln-Phe-Lys-NH2 (2) was further investigated for in vivo release of morphine. The antinociceptive effects following subcutaneous injection of the morphine-containing hydrogel 2 was evaluated in a model of thermal nociception using the mouse tail-flick test. Sustained antinociceptive effects over extended periods of time (up to 24 h) for morphine co-formulated with hydrogel 2, compared to morphine injection in solution (effects up to 2 h), were observed.