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

We propose using halogenated organic dyes as nanoprobes for electric field 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 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 synthesis of 3-fluoroterrylene and bulk spectroscopy of this compound in liquid and solid organic environments.Comment: Article presented in Faraday Discussions on September 201

Synthesis of phosphinic acid analogues of anti-tumour agents

Synthetic ether analogues (prototypes: miltefosine, perifosine and cdelfosine) of natural phospholipids are a family of anti-cancer drugs with a wide range of pharmacological behaviour. There is a growing interest in anti-cancer ether phospholipids owing to their seleC;!1vity against tumours which has resulted in a much lower toxicity, as compared with other classical anti-cancer chemotherapeutic agents. However, due to the presence of the phosphate diester, these compounds can be quickly biodegraded by enzymes of phospholipid metabolism. Consequently, the aims of this research project were to synthesise isosteric analogues of miltefosine, perifosine and edelfosine by replacing the two phosphorus-oxygen bonds with phosphorus-carbon bonds. Several methodologies for the preparation of phosphorus-carbon bonds were investigated and phosphinic acid analogues of miltefosine, perifosine and edelfosine were efficiently synthesised in good overall yields. The first phosphorus-carbon bond of miltefosine and edelfosine analogues was prepared by a radical hydrophosphorylation addition reaction, and the second by conversion to the P(III) silyloxy intermediate, followed by Michael-type addition to acrylonitrile and acidic hydrolysis of the silyl groups. Miltefosine analogue was synthesised in a total of six steps from hexadecene, in 69% overall yield, and edelfosine analogue was synthesised in a total of ten steps from hexadecanol, in 8.5% overall yield. Perifosine analogue was successfully synthesised by a double radical hydrophosphorylatipn process, in a total of six steps, in 50% overall yield from hexadecene.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Oxidative cyclodehydrogenation of a perylene derivative: different reagents give different products

cited By 4International audienceAn efficient synthesis of 3-fluoroterrylene, a promising molecular nanoprobe for single electron optical sensing, is described. The key synthetic steps comprised the palladium-catalysed cross-coupling reaction of 3-bromoperylene and 4-fluoronaphthalene-1-boronic acid pinacol ester to give 3-(4-fluoronaphthalen-1-yl)perylene, followed by oxidative cyclodehydrogenation to give selectively either 3-fluoroterrylene or its isomer 10-fluorobenzo[4,5]indeno[1,2,3-cd]perylene. The selectivity of the Scholl oxidation under AlCl3/chlorobenzene or DDQ/TfOH conditions was confirmed by 19F NMR

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

Abstract 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

The road to avibactam: The first clinically useful non-β-lactam working somewhat like a β-lactam

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

The road to avibactam: The first clinically useful non-β-lactam working somewhat like a β-lactam

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

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

International audienceDouble-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

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 [Zn4O(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 CO2 uptake and selective adsorption for it over CH4