Parahydrogen induced polarization in face of keto-enol tautomerism: proof of concept with hyperpolarized ethanol

Hyperpolarization (HP) techniques are increasingly important in magnetic resonance imaging (MRI) and spectroscopy (MRS). HP methods have the potential to overcome the fundamentally low sensitivity of magnetic resonance (MR). A breakthrough of HP-MR in life sciences and medical applications is still limited by the small number of accessible, physiologically relevant substrates. Our study presents a new approach to extend PHIP to substrates that primarily cannot be hyperpolarized due to a steady intramolecular re-arrangement, the so-called keto-enol tautomerism. To overcome this obstacle we exploited the fact that instead of the instable enol form the corresponding stable ester can be used as a precursor molecule. This strategy now enables the hydrogenation which is required to apply the standard PHIP procedure. As the final step a hydrolysis is necessary to release the hyperpolarized target molecule. Using this new approach ethanol was successfully hyperpolarized for the first time. It may therefore be assumed that the outlined multi-step procedure can be used for other keto-enol tautomerized substances thereby opening the application of PHIP to a multitude of molecules relevant to analyzing metabolic pathways.     

Tetrachlorinated tetraazaperopyrenes (TAPPs): highly fluorescent dyes and semiconductors for air-stable organic n-channel transistors and complementary circuits

A range of 2,9-perfluoroalkyl-substituted tetraazaperopyrene (TAPP) derivatives (1-5) was synthesised by reacting 4,9-diamino-3,10-perylenequinone diimine (DPDI) with the corresponding carboxylic acid chloride or anhydride in the presence of a base. The reaction of compounds 1-4 with dichloroisocyanuric acid (DIC) in concentrated sulphuric acid resulted in the fourfold substitution of the tetraazaperopyrene core, yielding the 2,9-bisperfluoroalkyl-4,7,11,14-tetrachloro-1,3,8,10-tetraazaperopyrenes 6-9, respectively. The optical and electrochemical data demonstrate the drastic influence of the core substitution on the properties. All compounds are highly luminescent (fluorescence quantum yields of up to Φ=0.8). The LUMO energies of the tetrachlorinated TAPP derivatives (determined by cyclic voltammetry and computed by DFT calulations) were found to be below -4?eV. In the course of this work the performance of TAPP derivatives in organic thin-film transistors (TFTs) was investigated, and their n-channel characteristics with field-effect mobilities of up to 0.14?cm(2) V(-1) s(-1) and an on/off current ratio of >10(6) were confirmed. Long-term stabilities of 3-4 months under ambient conditions of the devices were established. Complementary inverters and ring oscillators with n-channel TFTs based on compound 8 and p-channel TFTs based on dinaphtho-[2,3-b:2',3'-f]thieno[3,2-b]thiophene (DNTT) were fabricated on a glass substrate.     

Economic implications of poor access to antenatal care in rural and remote Western Australian Aboriginal communities: An individual sampling model of pregnancy

Background

Australian Aboriginal women attend antenatal care less frequently and experience poorer pregnancy outcomes than non-Aboriginal women. Improving access to antenatal care is recognised as a means to improve pregnancy outcomes for mother and baby.

Objective

To estimate the costs of inadequate antenatal care and provide baseline measurements and implications for policy that targets improving access to care in rural and remote Western Australian (WA) Aboriginal communities.

Methods

An individual sampling model of pregnancy was developed that simulated hypothetical women with pregnancy events and outcomes observed in the WA Aboriginal population. Weekly pregnancy events were modelled via logistic regression according to maternal characteristics, events during pregnancy and current gestation, with adequate and inadequate care (?4 and <4 antenatal visits) to reflect differences in outcomes reported in the literature. The pregnancy model simulated clinical management including antenatal visits, hospitalisations, and transfers to tertiary care.

Results

The mean cost of pregnancy was AUD$8985, with a large difference depending on access to antenatal care (AUD$7635 and AUD$10,216 for adequate and inadequate care respectively). The main difference in costs resulted from neonatal care (AUD$1021 vs AUD$3205 for adequate and inadequate care respectively). In a rural community with 150 births per year, up to AUD$123,082 may be spent to improve access to care at no extra cost to the total current expenditure (AUD$1,347,733).

Conclusions

The large difference in pregnancy costs between those receiving adequate and inadequate care demonstrates that additional expenditure on improving access to antenatal care may be cost-effective and should be further investigated.     

pH-induced release from P2VP-PEO block copolymer vesicles

The pH-induced release of hydrophilic dyes from poly(2-vinylpyridine-b-ethylene oxide) (P2VP-PEO) block copolymer vesicles is investigated. The structure of the vesicles is characterized using small-angle neutron scattering (SANS) and cryo-electron microscopy (cryo-TEM). A decrease of the pH below 5 leads to protonation and dissolution of the poly-2-vinylpyridine blocks which induces rupture and dissolution of the vesicle membrane. Details of the rupture, dissolution, and release process are studied by fluorescence video microscopy, gel electrophoresis, and high-performance ultrafiltration.     

Bifunctional charge transfer operated fluorescent probes with acceptor and donor receptors. 1. Biphenyl-type sensor molecules with protonation-induced anti-energy gap rule behavior

On the basis of biphenyl (b) type molecules bpb-R substituted with a 2,2':6',2' '-terpyridine acceptor (bp) and either amino-type donor receptors (R = dimethylamino (DMA), A15C5 = monoaza-15-crown-5) or nonbinding substituents (R = CF(3), H, OMe) of various donor strengths, we developed a family of charge transfer (CT) operated monofunctional and bifunctional fluorescent sensors for protons and metal ions. These molecules are designed to communicate the interaction of an analyte with the acceptor and the donor receptor differing in basicity and cation selectivity by clearly distinguishable spectral shifts and intensity modulations in absorption and in emission as well as in fluorescence lifetime. From the dependence of the fluorescence spectra, fluorescence quantum yields, and fluorescence lifetimes of bpb-R on solvent polarity and proton concentration, the photophysics of bpb-R and their protonated analogues can be shown to be governed by the relaxation to a CT state of forbidden nature and by the switching between anti-energy and energy gap law type behaviors. This provides the basis for analytically favorable red shifted emission spectra in combination with comparatively high fluorescence quantum yields. Accordingly, bpb-H and bpb-OMe are capable of ratiometric emission signaling of protons. bpb-DMA reveals a protonation-induced ON-OFF-ON switching of its emission.     

Supramolecular Nanocycles Comprising β‐Cyclodextrin‐click‐Ferrocene Units: Rings of Rings of Rings

We applied 1,3‐dipolar cycloaddition to bind ethynylferrocene onto 6I‐azido‐6I‐deoxycyclomaltoheptaose under microwave assisted conditions. The process was investigated by ¹H NMR, FT‐IR spectroscopy, and MALDI‐TOF mass spectrometry. The ability of the synthesized compound to self‐organize to cyclic supramolecular structures was investigated by dynamic light scattering measurements and cryo‐transmission electron microscopy.

     

1,3,6,8-Tetraazapyrenes: synthesis, solid-state structures, and properties as redox-active materials

A series of new tetraazapyrene (TAPy) derivatives has been synthesized by reducing 1,4,5,8-tetranitronaphthalene to its corresponding tin salt (I) and reacting it with perfluorinated alkyl or aryl anhydrides. The resulting 2,7-disubstituted TAPy molecules and the known parent compound 1,3,6,8-tetraazapyrene (II) have been further derivatized by core chlorination and bromination. The brominated compounds served as starting materials for Suzuki cross-coupling reactions with electron-poor arylboronic acids. Single-crystal X-ray analyses established polymorphism for some TAPy compounds. The ground-state geometries of all new TAPy derivatives were modeled with DFT methods [B3PW91/6-31 g(d,p) and B3PW91/6-311+g(d,p)], especially focusing on the energies of the lowest unoccupied molecular orbital (LUMO) and the electron affinities (EA) of the molecules. The results of the calculations were confirmed experimentally by cyclic voltammetry to evaluate the substitution effects at the 2 and 7 position and the core positions, respectively, and gave LUMO energy levels that range from -3.57 to -4.14 eV. Fabrication of organic field-effect transistors (OFETs) with several of these tetraazapyrenes established their potential as organic n-type semiconductors.     

A designer bleomycin with significantly improved DNA cleavage activity

The bleomycins (BLMs) are used clinically in combination with a number of other agents for the treatment of several types of tumors, and the BLM, etoposide, and cisplatin treatment regimen cures 90-95% of metastatic testicular cancer patients. BLM-induced pneumonitis is the most feared, dose-limiting side effect of BLM in chemotherapy, which can progress into lung fibrosis and affect up to 46% of the total patient population. There have been continued efforts to develop new BLM analogues in the search for anticancer drugs with better clinical efficacy and lower lung toxicity. We have previously cloned and characterized the biosynthetic gene clusters for BLMs from Streptomyces verticillus ATCC15003, tallysomycins from Streptoalloteichus hindustanus E465-94 ATCC31158, and zorbamycin (ZBM) from Streptomyces flavoviridis SB9001. Comparative analysis of the three biosynthetic machineries provided the molecular basis for the formulation of hypotheses to engineer novel analogues. We now report engineered production of three new analogues, 6'-hydroxy-ZBM, BLM Z, and 6'-deoxy-BLM Z and the evaluation of their DNA cleavage activities as a measurement for their potential anticancer activity. Our findings unveiled: (i) the disaccharide moiety plays an important role in the DNA cleavage activity of BLMs and ZBMs, (ii) the ZBM disaccharide significantly enhances the potency of BLM, and (iii) 6'-deoxy-BLM Z represents the most potent BLM analogue known to date. The fact that 6'-deoxy-BLM Z can be produced in reasonable quantities by microbial fermentation should greatly facilitate follow-up mechanistic and preclinical studies to potentially advance this analogue into a clinical drug.