Synthesis of tetraazamacrocyclic complexes: Biomedical applications

Tetraazamacrocyclic frameworks of 1,4,7,10-tetraazacylcododecane (cyclen) and 1,4,8,11-tetraazacyclotetradecane (cyclam) with functional pendent arms and porphyrins with solubilising polyethylene glycol (PEG) chains have been synthesised. The pendent arms possess different properties which tailor the metal complex towards a particular role

Perspective on the Hyperpolarisation Technique Signal Amplification by Reversible Exchange (SABRE) in NMR Spectroscopy and MR Imaging

Signal amplification by reversible exchange (SABRE) is a para-hydrogen-based technique that utilises a metal complex, normally centred on iridium, to propagate polarisation from para-hydrogen-derived hydride ligands to spin-1/2 nuclei located in a bound substrate. To date, substrates possessing 1 H, 13 C, 15 N, 19 F, 31 P, 29 Si, and 119 Sn nuclei have been polarised by this technique. The exact positioning of these nuclei has a direct bearing on the enhancement observed and so substrates must be chosen or synthesised with care in order to maximise polarisation transfer, and hence the resulting enhancement. The chemical composition of the metal complex must be similarly appraised, as the exchange rate of substrates and para-hydrogen is implicated heavily in efficient polarisation transfer. The nature of the polarisation transfer, whether homogenous or heterogeneous, is another important facet to consider here, as is conducting SABRE in water-based systems. This review discusses the physical and theoretical aspects of the SABRE experiment, as well as the applications of the SABRE technique, namely, the detection of analytes at concentrations far below what would be possible with conventional NMR techniques and the collection of hyperpolarised magnetic resonance images. Advances relating to utilising singlet states for SABRE, pulse sequence design and the nature of the polarisation transfer mechanism are also discussed, and the implications for future SABRE-based discoveries highlighted

1,8-bis(2-hydroxy-3,5-di-tert-butylbenzyl)-4,11-dibenzyl-1,4,8,11-tetraazacyclotetradecane

A cyclam (1,4,8,11-tetraazacyclotetradecane)-based macrocycle bearing two benzyl and two 2-hydroxy-3,5-di-tert-butylbenzyl pendent arms was synthesized and characterized using spectroscopic techniques and single crystal X-ray diffraction. The macrocycle crystallizes in the triclinic space group P-1, with the asymmetric unit containing one-half of the molecule. The structure is stabilized by hydrogen-bonding which exists between the phenolic protons and the nitrogen atoms of the macrocyclic ring. The presence of this hydrogen bonding is observed in the 1H-NMR due to the deshielded nature of the phenolic OH peak (δ 9.99). Cyclic voltammetry of the ligand revealed a single quasi-reversible peak at −0.58 V (Epc = −0.48 V and Epa = −0.68 V), which is due to the electrochemical oxidation of the phenol to the phenoxyl radical

Bacterial dominance is due to effective utilisation of secondary metabolites produced by competitors.

Interactions between bacteria govern the progression of respiratory infections; however, the mechanisms underpinning these interactions are still unclear. Understanding how a bacterial species comes to dominate infectious communities associated with respiratory infections has direct relevance to treatment. In this study, Burkholderia, Pseudomonas, and Staphylococcus species were isolated from the sputum of an individual with Cystic Fibrosis and assembled in a fully factorial design to create simple microcosms. Measurements of growth and habitat modification were recorded over time, the later using proton Nuclear Magnetic Resonance spectra. The results showed interactions between the bacteria became increasingly neutral over time. Concurrently, the bacteria significantly altered their ability to modify the environment, with Pseudomonas able to utilise secondary metabolites produced by the other two isolates, whereas the reverse was not observed. This study indicates the importance of including data about the habitat modification of a community, to better elucidate the mechanisms of bacterial interactions

Delivering strong 1H nuclear hyperpolarization levels and long magnetic lifetimes through signal amplification by reversible exchange

Hyperpolarization turns typically weak NMR and MRI responses into strong signals so that ordinarily impractical measurements become possible. The potential to revolutionize analytical NMR and clinical diagnosis through this approach reflect this area's most compelling outcomes. Methods to optimize the low cost parahydrogen based approach signal amplification by reversible exchange (SABRE) with studies on a series of biologically relevant nicotinamides and methyl nicotinates are detailed. These procedures involve specific 2H-labelling in both the agent and catalyst and achieve polarization lifetimes of ca. 2 minutes with 50% polarization in the case of 4,6-d2-methylnicotinate. As a 1.5 T hospital scanner has an effective 1H polarization level of just 0.0005% this strategy should result in compressed detection times for chemically discerning measurements that probe disease. To demonstrate this techniques generality, we exemplify further studies on a range of pyridazine, pyrimidine, pyrazine and isonicotinamide analogues that feature as building blocks in biochemistry and many disease treating drugs

Synthesis and hyperpolarisation of eNOS substrates for quantification of NO production by 1H NMR spectroscopy

Hyperpolarization enhances the intensity of the NMR signals of a molecule, whose in vivo metabolic fate can be monitored by MRI with higher sensitivity. SABRE is a hyperpolarization technique that could potentially be used to image nitric oxide (NO) production in vivo. This would be very important, because NO dysregulation is involved in several pathologies, including cardiovascular ones. The nitric oxide synthase (NOS) pathway leads to NO production via conversion of l-arginine into l-citrulline. NO is a free radical gas with a short half-life in vivo (≈5s), therefore direct NO quantification is challenging. An indirect method - based on quantifying conversion of an l-Arg- to l-Cit-derivative by 1H NMR spectroscopy - is herein proposed. A small library of pyridyl containing l-Arg derivatives was designed and synthesised. In vitro tests showed that compounds 4a-j and 11a-c were better or equivalent substrates for the eNOS enzyme (NO2 - production=19-46μM) than native l-Arg (NO2 - production=25μM). Enzymatic conversion of l-Arg to l-Cit derivatives could be monitored by 1H NMR. The maximum hyperpolarization achieved by SABRE reached 870-fold NMR signal enhancement, which opens up exciting future perspectives of using these molecules as hyperpolarized MRI tracers in vivo

Benchtop NMR analysis of piperazine-based drugs hyperpolarised by SABRE

Piperazine-based drugs, such as N-benzylpiperazine (BZP), became attractive in the 2000s due to possessing effects similar to amphetamines. Herein, BZP, in addition to its pyridyl analogues, 2-, 3- and 4-pyridylmethylpiperidine (2-PMP, 3-PMP and 4-PMP respectively) were subjected to the hyperpolarisation technique SABRE (Signal Amplification By Reversible Exchange) in order to demonstrate the use of this technique to detect these piperazine-based drugs. Although BZP was not hyperpolarised via SABRE, 2-PMP, 3-PMP and 4-PMP were, with the ortho- and meta-pyridyl protons of 4-PMP showing the largest enhancement of 313-fold and 267-fold respectively in a 1.4 T detection field, following polarisation transfer at earth's magnetic field. In addition to the freebase, 4-PMP.3HCl was also appraised by SABRE and was found not to polarise, however, the addition of increasing equivalents of triethylamine (TEA) produced the freebase, with a maximum enhancement observed upon the addition of three equivalents of TEA. Further addition of TEA led to a reduction in the observed enhancement. SABRE was also employed to polarise 4-PMP.3HCl (ca. 20% w/w) in a simulated tablet to demonstrate the forensic application of the technique (138-fold enhancement for the ortho-pyridyl protons). The amount of 4-PMP.3HCl present in the simulated tablet was quantified via NMR using D2 O as a solvent and compared well to complimentary GC-MS data. Exchanging D2 O for CD3 OD as the solvent utilised for analysis resulted in a significantly lower amount of 4-PMP.3HCl being determined, thus highlighting safeguarding issues linked to drug abuse in relation to determining the amount of active pharmaceutical ingredient present

The Role of Pressure in Inverse Design for Assembly

Isotropic pairwise interactions that promote the self assembly of complex particle morphologies have been discovered by inverse design strategies derived from the molecular coarse-graining literature. While such approaches provide an avenue to reproduce structural correlations, thermodynamic quantities such as the pressure have typically not been considered in self-assembly applications. In this work, we demonstrate that relative entropy optimization can be used to discover potentials that self-assemble into targeted cluster morphologies with a prescribed pressure when the iterative simulations are performed in the isothermal-isobaric ensemble. By tuning the pressure in the optimization, we generate a family of simple pair potentials that all self-assemble the same structure. Selecting an appropriate simulation ensemble to control the thermodynamic properties of interest is a general design strategy that could also be used to discover interaction potentials that self-assemble structures having, for example, a specified chemical potential.Comment: 29 pages, 8 figure