Organic & Biomolecular Chemistry Blog

Scientists in Germany have worked on optimising compounds that reduce the formation of amyloid β-peptides, which play a crucial role in the development and progression of Alzheimer’s disease. The team varied the membrane anchor, spacer and pharmacophore building blocks on BACE1 inhibitors to make tripartite structures (assembled by covalent coupling of BACE1 inhibitors with membrane anchors via suitable spacers).

Several BACE1 inhibitors have already been reported, but here, the team has shown that the cellular activity of small-molecule BACE1 inhibitors can be significantly increased by membrane targeting via a spacer with a raftophilic membrane anchor.

Optimisation of BACE1 Inhibition of Tripartite Structures by Modification of Membrane Anchor, Spacer and Pharmacophore – Development of Potential Agents for the Treatment of Alzheimer’s Disease
Hans-Joachim Knölker
DOI: 10.1039/C2OB26103K

Chemistry for Tomorrow’s World 2012: Using Chemistry to Improve Agricultural Productivity

6 pm, 26 September 2012
Chemistry Centre, Burlington House, London

Join us at the RSC’s Chemistry Centre in London to hear about how synthetic organic chemistry can help to feed the world.

Azoxystrobin is the world’s leading agricultural fungicide. It is a fully synthetic compound, whose invention was inspired by the structure and activity of the naturally-occurring fungicide strobilurin A. Today it is used worldwide to control fungi growing on over 120 types of crop, improving plant health, raising quality and increasing yield. The success of the project highlights the crucial importance of chemistry in meeting grand challenges such as global food security and the broader applicability of skills such as natural product synthesis. Our keynote speaker Dr John Clough led the team of chemists at Syngenta that invented azoxystrobin. He will discuss the key role that synthetic organic chemistry played in creating an effective and safe fungicide.

This event will be held in the Chemistry Centre on 26 September at the RSC’s recently refurbished building in Burlington House, London. Doors will open at 17:30 for refreshments. The event will begin at 18:00 and will finish with a wine reception. Please follow the link here for information and to register for the event.

During the Trojan war, Greeks built a huge wooden horse, hid men inside it and left it outside the city of Troy. The Trojans, claiming it as a victory trophy, brought it into their city. That night, the Greek force crept out of the horse, opened the gates for the rest of the Greek army and they destroyed the city of Troy

The emergence of drug resistant bacterial strains has led to an urgent need for new antibiotic agents. Scientists in the US are utilising the iron uptake pathway of Mycobacterium tuberculosis as a ‘Trojan horse’ approach to tuberculosis treatment.

Marvin Miller at the University of Notre Dame and colleagues have synthesised analogues of iron scavenging compounds that contain a maleimide functional group for future drug conjugation. Miller explains that these compounds will be actively assimilated by the M. tuberculosis pathogen by the active iron transport system, but can also carry a lethal agent into the pathogen.

One of the challenges of synthesising drug conjugates is finding a suitable functional group to attach the drug to the conjugate. The maleimide functionalised mycobactin analogue synthesised by the team simplifies the synthetic route by reducing the need for protecting groups. Thiol-maleimide chemistry can then be used to attach the drug.

Derek Tan, an expert in rational drug design at the Memorial Sloan–Kettering Cancer Center, US, is enthusiastic about the work. He believes that the advantage of the maleimide functional group is that it can react with nucleophiles, which may already be present in a potential conjugate drug, as opposed to electrophiles, which generally need to be synthetically introduced into the conjugate drug. This maleimide–mycobactin analogue ‘will enable the future synthesis of a wider array of potential Trojan horse antibiotics’, says Tan.

Miller and co-workers found that the maleimide–mycobactin analogue displayed antibiotic activity against Mycobacterium tuberculosis, but it was inactive against a broad panel of Gram-positive and Gram-negative bacteria. ‘The use of siderophores [iron chelating compounds] to deliver antibiotics exclusively into a single type of bacteria (e.g., Mtb, P. aeruginosa, E. coli), could reduce the administration of broad-spectrum antibiotics, minimising exposure and therefore the development of drug resistance’ says Miller.

In the future, the team intends to use a rational approach for selecting drugs to attach to the maleimide–mycobactin analogue, starting with drugs that inhibit essential survival processes.

References
1. R E Juárez-Hernández, S G Franzblau and M J Miller, Org. Biomol. Chem., 2012, DOI: 10.1039/c2ob26077h

2. Chemistry World story by Alisa Becker

Scientists in Switzerland have synthesised a dye (3,4:3’,4’-bibenzo[b]thiophene-2,2’-disulfonate) that can be used as a sensitive and selective molecular probe for the fluorimetric detection of caffeine in water.

The system’s sensitivity and selectivity are higher than those of current synthetic caffeine sensors, so much so that caffeine can be detected in the sub-millimolar concentration range, the researchers claim. The team prepared sensor test strips on which a change in emission colour on addition of caffeine was easy to detect by the naked eye.

A ratiometric fluorescence sensor for caffeine
Nicolas Luisier, Albert Ruggi, Stephan N. Steinmann, Laurane Favre, Nicolas Gaeng, Clémence Corminboeuf and Kay Severin
DOI: 10.1039/C2OB26117K