Antimicrobial polymers prepared by ROMP with unprecedented selectivity: a molecular construction kit approach

Synthetic Mimics of Antimicrobial Peptides (SMAMPs) imitate natural host-defense peptides, a vital component of the body's immune system. This work presents a molecular construction kit that allows the easy and versatile synthesis of a broad variety of facially amphiphilic oxanorbornene-derived monomers. Their ring-opening metathesis polymerization (ROMP) and deprotection provide several series of SMAMPs. Using amphiphilicity, monomer feed ratio, and molecular weight as parameters, polymers with 533 times higher selectivitiy (selecitviy = hemolytic concentration/minimum inhibitory concentration) for bacteria over mammalian cells were discovered. Some of these polymers were 50 times more selective for Gram-positive over Gram-negative bacteria while other polymers surprisingly showed the opposite preference. This kind of "double selectivity" (bacteria over mammalian and one bacterial type over another) is unprecedented in other polymer systems and is attributed to the monomer's facial amphiphilicity.     

Nanoscale co-organization of quantum dots and conjugated polymers using polymeric micelles as templates

Hierarchical organization of light-absorbing molecules is integral to natural light harvesting complexes and has been mimicked by elegant chemical systems. A challenge is to attain such spatial organization among nanoscale systems. Interactions between nanoscale systems, e.g., conjugated polymers, carbon nanotubes, quantum dots, and so on, are of interest for basic and applied reasons. However, typically the excited-state interactions and dynamics are examined in rather complex blends, such as cast films. A model system with complexity intermediate between a film and a supramolecular system would yield helpful insights into electronic energy and charge transfer. Here, we report a simple and versatile approach to achieving spatially defined organization of colloidal CdSe, CdSe/ZnS core/shell, or PbS nanocrystals (quantum dots) with poly(3-hexylthiophenes) (P3HTs) using micelles of poly(styrene-b-4-vinylpyridine) (PS-b-P4VP) as the main structural motif. We compare the characteristics of this system to those of natural light-harvesting complexes. Bulk heterojunction films (and related systems) are characterized by electronic interactions, and therefore dynamics of charge and energy transfer, at interfaces rather than between specific donor-acceptor molecules. Owing to structural disorder, such systems are inherently complex. Therefore, we expect that the spatially defined organization of the active components in the present system provides new opportunities for studying the complicated photophysics intrinsic to blends of nanoscale systems, such as bulk heterojunctions by establishing simplified and better controlled interfaces.     

Laterally nanostructured adsorbed layers of surfactant/surfmer mixtures before and after polymerisation

The adsorbed layer structure of mixed films of the polymerisable cationic surfactant dodecyldimethyl(ethylmethacrylate)ammonium bromide (MEDDAB) with the cationic and non-ionic surfactants dodecyltrimethylammonium bromide (DTAB) and polyoxyethylene-23-lauryl ether (C12E23) has been investigated by AFM soft-contact imaging before and after solution polymerisation of MEDDAB. MEDDAB alone adsorbs on mica as a planar bilayer, but the adsorbed layer structure can be modified by mixing with DTAB or C12E23 to yield an adsorbed mesh or cylinders. The equilibrium adsorbed film structure after solution polymerisation of the methacrylate group on MEDDAB was found to depend on the solubilising ability of the non-polymerisable surfactant. C12E23 effectively prevented precipitation of polymerised MEDDAB, retaining the unpolymerised adsorbed layer structure, whereas DTAB mixtures became cloudy above 23 mol% MEDDAB. The resultant structure remained similar to the adsorbed rods formed prior to polymerisation, but had a diameter several times larger.     

Catalase-peroxidase activity of iron(III)-TAML activators of hydrogen peroxide

Exceptionally high peroxidase-like and catalase-like activities of iron(III)-TAML activators of H 2O 2 ( 1: Tetra-Amidato-Macrocyclic-Ligand Fe (III) complexes [ F e{1,2-X 2C 6H 2-4,5-( NCOCMe 2 NCO) 2CR 2}(OH 2)] (-)) are reported from pH 6-12.4 and 25-45 degrees C. Oxidation of the cyclometalated 2-phenylpyridine organometallic complex, [Ru (II)( o-C 6H 4py)(phen) 2]PF 6 ( 2) or "ruthenium dye", occurs via the equation [ Ru II ] + 1/2 H 2 O 2 + H +-->(Fe III - TAML) [ Ru III ] + H 2 O, following a simple rate law rate = k obs (per)[ 1][H 2O 2], that is, the rate is independent of the concentration of 2 at all pHs and temperatures studied. The kinetics of the catalase-like activity (H 2 O 2 -->(Fe III - TAML) H 2 O + 1/2 O 2) obeys a similar rate law: rate = k obs (cat)[ 1][H 2O 2]). The rate constants, k obs (per) and k obs (cat), are strongly and similarly pH dependent, with a maximum around pH 10. Both bell-shaped pH profiles are quantitatively accounted for in terms of a common mechanism based on the known speciation of 1 and H 2O 2 in this pH range. Complexes 1 exist as axial diaqua species [FeL(H 2O) 2] (-) ( 1 aqua) which are deprotonated to afford [FeL(OH)(H 2O)] (2-) ( 1 OH) at pH 9-10. The pathways 1 aqua + H 2O 2 ( k 1), 1 OH + H 2O 2 ( k 2), and 1 OH + HO 2 (-) ( k 4) afford one or more oxidized Fe-TAML species that further rapidly oxidize the dye (peroxidase-like activity) or a second H 2O 2 molecule (catalase-like activity). This mechanism is supported by the observations that (i) the catalase-like activity of 1 is controllably retarded by addition of reducing agents into solution and (ii) second order kinetics in H 2O 2 has been observed when the rate of O 2 evolution was monitored in the presence of added reducing agents. The performances of the 1 complexes in catalyzing H 2O 2 oxidations are shown to compare favorably with the peroxidases further establishing Fe (III)-TAML activators as miniaturized enzyme replicas with the potential to greatly expand the technological utility of hydrogen peroxide.     

A sensitive assay for the quantification of morphine and its active metabolites in human plasma and dried blood spots using high-performance liquid chromatography–tandem mass spectrometry

Opioids such as morphine are the cornerstone of pain treatment. The challenge of measuring the concentrations of morphine and its active metabolites in order to assess human pharmacokinetics and monitor therapeutic drugs in children requires assays with high sensitivity in small blood volumes. We developed and validated a semi-automated LC-MS/MS assay for the simultaneous quantification of morphine and its active metabolites morphine 3β-glucuronide (M3G) and morphine 6β-glucuronide (M6G) in human plasma and in dried blood spots (DBS). Reconstitution in water (DBS only) and addition of a protein precipitation solution containing the internal standards were the only manual steps. Morphine and its metabolites were separated on a Kinetex 2.6-μm PFP analytical column using an acetonitrile/0.1% formic acid gradient. The analytes were detected in the positive multiple reaction mode. In plasma, the assay had the following performance characteristics: range of reliable response of 0.25–1000 ng/mL (r ² > 0.99) for morphine, 1–1,000 ng/mL (r ² > 0.99) for M3G, and 2.5–1,000 ng/mL for M6G. In DBS, the assay had a range of reliable response of 1–1,000 ng/mL (r ² > 0.99) for morphine and M3G, and of 2.5–1,000 ng/mL for M6G. For inter-day accuracy and precision for morphine, M3G and M6G were within 15% of the nominal values in both plasma and DBS. There was no carryover, ion suppression, or matrix interferences. The assay fulfilled all predefined acceptance criteria, and its sensitivity using DBS samples was adequate for the measurement of pediatric pharmacokinetic samples using a small blood of only 20–50 μL.     

Characterization of a core fragment of the rhesus monkey TRIM5α protein

Background  

Like all tripartite motif (TRIM) proteins, the retroviral restriction factor TRIM5α consists of RING, B-box 2 and coiled-coil domains, with a C-terminal B30.2(SPRY) domain. Although structures have been determined for some individual TRIM domains, the structure of an intact TRIM protein is unknown.     

Synthesis of the tricyclic core of aldingenin B by oxidative cyclo-ketalization of an alkyne-diol

The preparation and selenium-mediated cyclo-ketalization of an alkyne-diol is described as a model study for the synthesis of aldingenin B. The oxidative cyclization is a simplifying transformation for aldingenin B, as it provides a convenient method for generating the tricylic core of the natural product from a functionalized cyclohexane.     

Lewis acid adducts of narrow band gap conjugated polymers

We report on the interaction of Lewis acids with narrow band gap conjugated copolymers containing donor and acceptor units. Examination of the widely used poly[(4,4-bis(2-ethylhexyl)cyclopenta-[2,1-b:3,4-b']dithiophene)-2,6-(diyl-alt-benzo[2,1,3]thiadiazole)-4,7-diyl] (1) shows weaker binding with B(C(6)F(5))(3) when compared with a small molecule that contains a cyclopenta-[2,1-b:3,4-b']dithiophene (CDT) unit flanked by two benzo[2,1,3]thiadiazole (BT) fragments. Studies on model compounds representative of 1, together with a comparison between B(C(6)F(5))(3) and BBr(3), indicate that the propensity for Lewis acid coordination is decreased because of steric encumbrance surrounding the BT nitrogen sites. These observations led to the design of chromophores that incorporate an acceptor unit with a more basic nitrogen site, namely pyridal[2,1,3]thiadiazole (PT). That this strategy leads to a stronger B-N interaction was demonstrated through the examination of the reaction of B(C(6)F(5))(3) with two small molecules bis(4,4-bis(hexyl)-4H-cyclopenta[2,1-b;3,4-b']dithiophene)-4,7-pyridal[2,1,3]thiadiazole (8) and bis{2-thienyl-(4,4-bis(hexyl)-4H-cyclopenta[2,1-b;3,4-b']dithiophene)}-4,7-pyridal[2,1,3]thiadiazole (9) and two polymer systems (poly[(4,4-bis(2-ethylhexyl)cyclopenta-[2,1-b:3,4-b']dithiophene)-2,6-diyl-alt-([1,2,5]thiadiazolo[3,4-c]pyridine)-4,7-diyl] (10) and poly[(4,4-bis(2-ethylhexyl)cyclopenta-[2,1-b:3,4-b']dithiophene)-2,6-diyl-alt-(4',7'-bis(2-thienyl)-[1,2,5]thiadiazolo[3,4-c]pyridine)-5,5-diyl] (11). From a materials perspective, it is worth pointing out that through the binding of B(C(6)F(5))(3), new NIR-absorbing polymers can be generated with band gaps from 1.31 to 0.89 eV. A combination of studies involving ultraviolet photoemission spectroscopy and density functional theory shows that the narrowing of the band gap upon borane coordination to the pyridal nitrogen on PT is a result of lowering the energies of both the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) of the optically relevant fragments; however, the LUMO is decreased to a greater extent, thereby giving rise to the narrowing of the gap.     

Cobalt‐mediated radical polymerization routes to poly(vinyl ester) block copolymers

Cobalt‐mediated radical polymerizations (CMRPs) utilizing redox initiation are demonstrated to produce poly(vinyl ester) homopolymers derived from vinyl pivalate (VPv) and vinyl benzoate (VBz), and their block copolymers with vinyl acetate (VAc). Combining anhydrous Co(acac)₂, lauroyl peroxide, citric acid trisodium salt, and VPv at 30 °C results in controlled polymerizations that yield homopolymers with M_n = 2.5–27 kg/mol with M_w/M_n = 1.20–1.30. Homopolymerizations of scrupulously purified VBz proceed with lower levels of control as evidenced by broader polydispersities over a range of molecular weights (M_n = 4–16 kg/mol; M_w/M_n = 1.34–1.65), which may be interpreted in terms of the decreased nucleophilicity of these less electron donating propagating polymer chain ends. Based on these results, we demonstrate that sequential CMRP reactions present a viable route to microphase separated poly(vinyl ester) block copolymers as shown by small‐angle X‐ray scattering analyses. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2010     

Consolidating molecular AND logic with two chemical inputs

A novel molecular AND logic gate 1 is demonstrated based on the competition between fluorescence and photoinduced electron transfer (PET). It is constructed according to a 'receptor2-spacer-fluorophore-spacer-receptor1-spacer-fluorophore-spacer-receptor2' format where receptor1 is a tertiary amine, receptor2 is a benzo-15-crown-5 ether and the fluorophore is an anthracene moiety, which are separated from each other by methylene spacers. The fluorescence response in methanol is significantly enhanced only when both H+ and Na+ are the inputs at high enough concentrations in accordance with AND logic. Cs+ behaves similarly to Na+, but with a lower fluorescence enhancement, whereas the other alkali metal cations are not effective. Electrospray ionization mass spectrometry provides evidence for formation of 1:1 and 1:2 (1:metal) complexes with alkali cations, and formation of a 1:2:1 (1:metal:proton) complex in the additional presence of acid.