Chemical Science Blog

US scientists have synthesised by a new route a key intermediate for the production of synthetic analogues of natural antibiotic tetracyclines that could be used as potential new drugs to combat the growing ranks of antibiotic resistant bacteria.

Andrew Myers and coworkers from Harvard University, Massachusetts, have developed a scalable five step route to an enone intermediate, which can be converted to a range of tetracyclines in three steps. The products are also crystalline at many stages, so there’s no need for purification by chromatography.

The team made the enone by coupling a cyclohexenone with an ester – two inexpensive starting materials made in a few steps from simple precursors. ‘We’ve reduced the problem of tetracycline synthesis to the synthesis of the enone, because from that molecule, you can make completely new tetracyclines,’ says Myers. ‘All tetracyclines that have been approved as drugs in the last 60 years have been made by semi-synthesis – in which fermentation products are used as starting materials – and chemists’ ability to modify these natural products has been limited. We wanted to see if we could develop a completely synthetic route.’

The enone intermediate, a precursor to tetracyclines, was made in five steps by coupling a cyclohexenone with an ester

Myers can now make tetracyclines with modifications all around the structure’s periphery and even in the interior portion. The reaction that transforms the enone into thousands of antibiotics is a Michael-Claisen cyclisation on the left side of the enone, he explains. But it’s also possible to use a similar transformation to modify the right side. ‘Because we’ve got a de novo construction of the enone, we can modify portions of the enone and greatly expand the number of new tetracyclines we can make. In fact, if you think about it, you realise it’s a multiplicative expansion because the expansions on the right side can be coupled with those on the left,’ explains Myers…

To read more, please visit the Chemistry World website or download the Chemical Science Edge Article, which is free to access until the end of 2011! 

The basic components of cells can operate within the bounds of inorganic membranes made from nanoparticles, a new study shows. The authors say such membranes provide an alternative model for explaining how the first cells evolved from simple, inorganic molecules.

Chemists created silicon-based membranes with hydrophilic and hydrophobic properties akin to those of lipid bilayers in natural cells. Nanoparticles self-assembled in oil to form ‘protocells’, enclosing drops of water inside porous silicon shells. ‘What was really interesting was that not only could we stabilise the droplets – which had been shown before – but that the nanoparticle-based shell could be considered as a primitive, semi-permeable inorganic membrane,’ says Stephen Mann, one of the researchers based at the University of Bristol, UK.

A simple reaction to functionalise the surface of the nanoparticle-stabilised droplets prevents entrapped biomolecules escaping into the water around them

To produce the desired water-loving/hating membrane, the researchers functionalised the surface of hydrophilic silica nanoparticles with silanol and dimethylsilane groups. Shaking the nanoparticles in oil and water made them pack together at the oil-water interface. According to Mann, the approach is simpler than chemical syntheses required to make artificial phospholipids, which are often used in artificial cell membranes…

To read more please visit the Chemistry World website, or you can download the Chemical Science Edge Article, which is free to access until the end of 2011!

Some Alzheimer’s drugs work by blocking the activity of acetylcholinesterase, an enzyme that degrades the neurotransmitter acetylcholine to choline. To find new enzyme inhibitors, researchers need to identify choline formation, or the loss of acetylcholine, so they can tell whether the enzymatic reaction has stopped. But, acetylcholine and choline are both quaternary ammonium ions with very similar structures, making it difficult to distinguish between them.

To overcome this problem, teams led by Werner Nau at Jacobs University Bremen, Germany, and Yu Liu at Nankai University, China, have combined two sequential enzymatic reactions with a calixarene macrocycle that binds to a fluorescent dye to make a tandem assay that can screen for new inhibitors. The enzymes are highly specific and only work on one substrate.

The tandem reaction involves a fluorescence ''switch-on'' displacement assay as a sensor for specific analytes

In their assay, they use acetylcholinesterase to turn acetylcholine to choline. A second enzyme – choline oxidase – turns the choline into betaine. While choline and betaine are similar, they have different affinities for binding within the calixarene. Because of this difference, the dye can replace the betaine inside the calixarene. This turns off the dye’s fluorescence, which is easy to detect. If the enzymatic reactions are inhibited, no betaine will be produced and so the dye’s fluorescence stays on……

To read the full story, please visit the Chemistry World website or download the Chemical Science Edge Article, which is free to access until the end of 2011!

An assay that combines enzymatic reactions with a fluorescent sensor could help discover new Alzheimer’s disease drugs. 

Acetylcholinesterase is an enzyme involved in the development of Alzheimer’s disease. Werner Nau and Yu Liu and their teams hope that their tandem assay could be used to search for new acetylcholinesterase inhibitors as potential drugs.

The simple, fluorescence based, tandem assay can measure micromolar concentrations of choline and acetylcholine or screen for enzyme inhibitors. The change in fluorescence is easy to detect, making the assay suitable for large scale screening. 

Reference:
Operational calixarene-based fluorescent sensing systems for choline and acetylcholine and their application to enzymatic reactions
D-S Guo, V D Uzunova, X Su, Y Liu and W M Nau, Chem. Sci., 2011, DOI: 10.1039/c1sc00231g

Nanoparticle probes for imaging cells can now be made more simply and quickly thanks to a new method reported by Chinese chemists. 

Gold nanoparticles have been widely used for bio-imaging but they need to be coated, commonly in silica, to protect them and stop them aggregating. The conventional method for silica coating is time-consuming but the team say they’ve overcome this tedious process by using an organosilica source. The resulting organosilica shell has –SH and –OH groups inside it, making it easy to functionalise with fluorescent dyes or biomolecules. 

By modifying the gold core with Raman reporters and the organosilica shell with a fluorophore, the group produced nanoparticles with three modalities of imaging – Rayleigh scattering, fluorescence and surface enhanced Raman scattering.

Reference:
Au@organosilica multifunctional nanoparticles for the multimodal imaging
Y Cui, X-S Zheng, B Ren, R Wang, J Zhang, N-S Xia and Z-Q Tian, Chem. Sci., 2011, DOI: 10.1039/c1sc00242b

Covalent organic frameworks (COFs) are an emerging class of porous materials with potential for gas storage and organic photovoltaics. Their development has been hampered because the building blocks most commonly used to make them are poorly soluble and prone to oxidation.

Now US chemists have developed a general strategy for making COFs from stable, soluble starting materials. They also gained insight into the transformation’s mechanism, which should help scientists predict crystallisation conditions and prepare materials with improved properties.

Find out more in A mechanistic study of Lewis acid-catalyzed covalent organic framework formation by William Dichtel and colleagues.

UK scientists have worked out how ionic liquids solubilise cellulose, an important step in biomass processing.

The precise mechanism for the dissolution of cellulose by ionic liquids is hotly debated, with some researchers insisting that the ionic liquid cation forms a hydrogen bond to the sugar’s OH groups, without data to back it up.

Now researchers have proved conclusively with experimental data that there are no hydrogen bonding interactions between the cation and the sugars.

Read Christopher Hardacre’s Chemical Science Edge article to find out more.

Also of interest:
How polar are ionic liquids? Solutions of charge-transfer salts in ionic liquids reveal a dual nature of solvent polarity and an absence of ion pairing

UK scientists have reported a novel, more general method for inserting a useful ‘tag’ into proteins, enabling easier protein modification.

Dehydroalanine is an amino acid residue and useful precursor to a range of post-translational modifications. Several chemical and biochemical methods for incorporating dehydroalanine into peptides and proteins have been reported but each strategy has its limitations, says Ben Davis, from the University of Oxford.

Davis’ team assessed the merits and drawbacks of these methods and came up with a more general method – the bis-alkylation-elimination of cysteine to dehydroalanine using a stable, easy to prepare dibromide compound.

To demonstrate the scope and utility of the method, they used it to incorporate the tag into an antibody, then glycosylated it.

To find out more about Professor Davis’ research, download his Chemical Science Edge article. You can also see him speak at Challenges in Chemical Biology (ISACS5) in Manchester in July – registration deadline 24th June 2011.