Structural analysis of the 2-oxoglutarate binding site of the circadian rhythm linked oxygenase JMJD5.

JmjC (Jumonji-C) domain-containing 5 (JMJD5) plays important roles in circadian regulation in plants and humans and is involved in embryonic development and cell proliferation. JMJD5 is a 2-oxoglutarate (2OG) and Fe(II) dependent oxygenase of the JmjC subfamily, which includes histone Nε-methyl lysine-demethylases (KDMs) and hydroxylases catalysing formation of stable alcohol products. JMJD5 is reported to have KDM activity, but has been shown to catalyse C-3 hydroxylation of arginine residues in sequences from human regulator of chromosome condensation domain-containing protein 1 (RCCD1) and ribosomal protein S6 (RPS6) in vitro. We report crystallographic analyses of human JMJD5 complexed with 2OG analogues, including the widely used hypoxia mimic pyridine-2,4-dicarboxylate, both D- and L-enantiomers of the oncometabolite 2-hydroxyglutarate, and a cyclic N-hydroxyimide. The results support the assignment of JMJD5 as a protein hydroxylase and reveal JMJD5 has an unusually compact 2OG binding pocket suitable for exploitation in development of selective inhibitors. They will be useful in the development of chemical probes to investigate the physiologically relevant roles of JMJD5 in circadian rhythm and development and explore its potential as a medicinal chemistry target.

On-Surface Synthesis of Chlorinated Narrow Graphene Nanoribbon Organometallic Hybrids.

Graphene nanoribbons (GNRs) and their derivatives attract growing attention due to their excellent electronic and magnetic properties as well as the fine-tuning of such properties that can be obtained by heteroatom substitution and/or edge morphology modification. Here, we introduce graphene nanoribbon derivatives-organometallic hybrids with gold atoms incorporated between the carbon skeleton and side Cl atoms. We show that narrow chlorinated 5-AGNROHs (armchair graphene nanoribbon organometallic hybrids) can be fabricated by on-surface polymerization with omission of the cyclodehydrogenation reaction by a proper choice of tailored molecular precursors. Finally, we describe a route to exchange chlorine atoms connected through gold atoms to the carbon skeleton by hydrogen atom treatment. This is achieved directly on the surface, resulting in perfect unsubstituted hydrogen-terminated GNRs. This will be beneficial in the molecule on-surface processing when the preparation of final unsubstituted hydrocarbon structure is desired.

A human protein hydroxylase that accepts D-residues.

Factor inhibiting hypoxia-inducible factor (FIH) is a 2-oxoglutarate-dependent protein hydroxylase that catalyses C3 hydroxylations of protein residues. We report FIH can accept (D)- and (L)-residues for hydroxylation. The substrate selectivity of FIH differs for (D) and (L) epimers, e.g., (D)- but not (L)-allylglycine, and conversely (L)- but not (D)-aspartate, undergo monohydroxylation, in the tested sequence context. The (L)-Leu-containing substrate undergoes FIH-catalysed monohydroxylation, whereas (D)-Leu unexpectedly undergoes dihydroxylation. Crystallographic, mass spectrometric, and DFT studies provide insights into the selectivity of FIH towards (L)- and (D)-residues. The results of this work expand the potential range of known substrates hydroxylated by isolated FIH and imply that it will be possible to generate FIH variants with altered selectivities.

Structure activity relationship studies on rhodanines and derived enethiol inhibitors of metallo-ß-lactamases.

Metallo-ß-lactamases (MBLs) enable bacterial resistance to almost all classes of ß-lactam antibiotics. We report studies on enethiol containing MBL inhibitors, which were prepared by rhodanine hydrolysis. The enethiols inhibit MBLs from different subclasses. Crystallographic analyses reveal that the enethiol sulphur displaces the di-Zn(II) ion bridging 'hydrolytic' water. In some, but not all, cases biophysical analyses provide evidence that rhodanine/enethiol inhibition involves formation of a ternary MBL enethiol rhodanine complex. The results demonstrate how low molecular weight active site Zn(II) chelating compounds can inhibit a range of clinically relevant MBLs and provide additional evidence for the potential of rhodanines to be hydrolysed to potent inhibitors of MBL protein fold and, maybe, other metallo-enzymes, perhaps contributing to the complex biological effects of rhodanines. The results imply that any medicinal chemistry studies employing rhodanines (and related scaffolds) as inhibitors should as a matter of course include testing of their hydrolysis products.

Construction of 2D nanoporous networks by coupling on-surface dynamic imine chemistry and dipole-stabilized self-assembly.

Double-walled nanoporous networks based on the Schiff base reaction of nonplanar tripodic building blocks and subsequent dipole-directed self-assembly were fabricated on highly oriented pyrolytic graphite (HOPG) at the gas-solid interface. This is the first example of nonplanar molecules exploited as precursors for a surface reaction.

The road to avibactam: the first clinically useful non-ß-lactam working somewhat like a ß-lactam.

Avibactam, which is the first non-ß-lactam ß-lactamase inhibitor to be introduced for clinical use, is a broad-spectrum serine ß-lactamase inhibitor with activity against class A, class C, and, some, class D ß-lactamases. We provide an overview of efforts, which extend to the period soon after the discovery of the penicillins, to develop clinically useful non-ß-lactam compounds as antibacterials, and, subsequently, penicillin-binding protein and ß-lactamase inhibitors. Like the ß-lactam inhibitors, avibactam works via a mechanism involving covalent modification of a catalytically important nucleophilic serine residue. However, unlike the ß-lactam inhibitors, avibactam reacts reversibly with its ß-lactamase targets. We discuss chemical factors that may account for the apparently special nature of ß-lactams and related compounds as antibacterials and ß-lactamase inhibitors, including with respect to resistance. Avenues for future research including non-ß-lactam antibacterials acting similarly to ß-lactams are discussed.

Design and synthesis of aromatic molecules for probing electric fields at the nanoscale.

We propose using halogenated organic dyes as nanoprobes for electric fields and show their greatly enhanced Stark coefficients using density functional theory (DFT) calculations. We analyse halogenated variants of three molecules that have been of interest for cryogenic single molecule spectroscopy: perylene, terrylene, and dibenzoterrylene, with the zero-phonon optical transitions at blue, red, and near-infrared. Out of all the combinations of halides and binding sites that are calculated, we have found that fluorination of the optimum binding site induces a dipole difference between the ground and excited states larger than 0.5 D for all three molecules with the highest value of 0.69 D for fluoroperylene. We also report on the synthesis of 3-fluoroterrylene and the bulk spectroscopy of this compound in liquid and solid organic environments.

Synthesis of a phosphinate analogue of the anti-tumour phosphate di-ester perifosine via sequential radical processes.

An efficient synthesis of a phosphinate analogue of the anti-tumour phosphate di-ester perifosine is described (6 steps and 50% overall yield). The two phosphorus-carbon bonds in the perifosine analogue were prepared by sequential double radical hydrophosphinylation processes. This is the first example of a phosphinate analogue of perifosine, designed to be resistant to hydrolysis by phospholipid-metabolizing enzymes.

One-pot regioselective synthesis and X-ray crystal structure of a stable [60]fullerene trisadduct with the e(edge),e(face),trans-1 addition pattern.

The Bingel functionalisation of C(60) with a structurally novel tether equipped with three reactive malonate groups afforded a C(2v)-symmetrical e(edge),e(face),trans-1 trisadduct in a complete regioselective manner and in an excellent yield of 65%. The [60]fullerene trisadduct showed pronounced ability to crystallise and gave X-ray quality single crystals for analysis.

A highly porous interpenetrated metal-organic framework from the use of a novel nanosized organic linker.

The initial use of a novel elongated tricarboxylic acid H(3)hmpib in metal-organic framework (MOF) chemistry resulted in a [Zn(4)O(hmpib)(2)] MOF (UCY-1) with pyrite topology. The compound displays a remarkably high internal surface area despite its double-interpenetrated structure as well as high CO(2) uptake and selective adsorption for it over CH(4).