Chemical Science Blog

UK researchers have embarked upon a new method to create structurally diverse molecules for drug discovery.

Finding new lead compounds for drug discovery is a formidable challenge which has traditionally relied on natural product isolation and combinatorial chemistry. Despite significant investment in combinatorial chemistry, this approach has found very limited success due to a lack of chirality and structural rigidity in the compounds produced. To tackle this problem, chemists are using diversity orientated synthesis (DOS) which aims to produce compounds that are structurally diverse in shape and stereochemistry and also in functionality.

Robert Stockman from the University of Nottingham and his team have pioneered an approach that combines two-directional synthesis with tandem reactions as a tool for DOS. The starting material is a simple trifunctional, linear molecule that can be folded back on itself in a number of ways to produce a wide range of structures – like tying knots in a piece of rope.

12 products are synthesised from one molecule by combining two-directional synthesis and tandem reactions

The researchers were able to create twelve natural product-like structures from only one compound, in just fifteen reactions. Stockman and his team found that a number of compounds derived from one of the products were effective against cancer cell lines, proving that compounds synthesised by this approach are promising candidates for use in new medicines.

To find out more, watch Dr Stockman’s video and download the Chemical Science Edge article.

Scientists from India and Denmark have found a way to go one better than x-ray crystallography to examine pharmaceutical crystals at an even deeper level. Their method could be used to distinguish between polymorphs – different crystal forms – of a compound to aid in drug design. 

The team, led by Upadrasta Ramamurty and Gautam Desiraju from the Indian Institute of Science, Bangalore, and Andrew Bond from the University of Southern Denmark, have used nanoindentation to analyse two different polymorphs of aspirin. Polymorphs are crystals of the same compound but with a different molecular arrangement. Although two crystals may appear similar in structure, they can have dramatically different properties, and many drugs only receive regulatory approval for one form. ‘One of the current areas of research is trying to link crystal properties to crystal structure and to try to understand how polymorphism occurs,’ says Bond.

The nanoidentation technique involves depressing a nano-sized tip into the crystal. The researchers then measured the imprint left in the sample to determine the material’s mechanical properties, such as plasticity and elasticity (how easily a substance is deformed permanently and non-permanently, respectively).

The team discovered that two polymorph crystals of aspirin, which appeared to be pure by x-ray crystallography, in fact contained a mixture of the polymorph types. Nanoindentation could have an impact on the pharmaceutical industry, which currently relies on x-ray crystallography to establish whether or not a new drug has been made, for intellectual property rights.

Read the full story in Chemistry World and find out more by downloading the Chemical Science Edge article.

US chemists have devised an efficient synthesis of a natural product with great potential as a protectant against chemical warfare agents and in the treatment of Alzheimer’s disease.

Huperzia serrata, one of an ancient lineage of plants known as the firmosses, has been much in demand lately because it contains a chemical known as (-)-huperzine A. This alkaloid is a potent and selective inhibitor of acetylcholine esterase, and as a result is able to counteract the action of certain chemical warfare agents, such as sarin and VX. There are also strong suggestions that it may slow the progression of neurological diseases such as Alzheimer’s disease. A team of organic chemists led by Seth Herzon at Yale University, New Haven, has now developed a high-yielding route to this elusive natural product, opening up opportunities for its wider clinical evaluation.

‘The primary obstacle to the clinical development of (-)-huperzine A has been one of supply,’ says Herzon. He points out that the average yield from the dried herb is just 0.011 per cent, a problem compounded by the nearly 20 years it takes to reach maturity, coupled with its increasing scarcity due to overharvesting in its native China.  To address these problems, several groups have in the past devised syntheses of (-)-huperzine A, with the best to date employing 16 steps and giving an overall yield of about 2.8 per cent. Herzon and his team have now beaten this by a factor of 16, with an eight-step synthesis that gives 25-45 per cent overall yield.

Read the full story in Chemistry World and download Herzon’s Chemical Science Edge article.

A team of researchers led by Takashi Nakanishi from the National Institute for Materials Science in Japan have made a nanocarbon hybrid of a C₆₀ derivative and single-walled carbon nanotube (SWCNT) to be used in photovoltaic devices.  The high performance of the nanomaterial is the result of a combination of the optical and electronic properties of the SWCNTs with the electron-accepting property of C₆₀.

Photoconductivity experiment using a field-effect transistor equipped with the carbon nanohybrid

The C₆₀ is decorated with long alkyl chains which have an affinity for the SWCNT surface, avoiding the problems associated with covalent functionalisation when combining such materials. By incorporating C₆₀ into the hybrid, the SWCNTs were soluble in organic solvents meaning classic wet processes can be used to fabricate the photovoltaic device.

The nanocarbon material also has the added benefit of being superhydrophobic, providing the device with waterproof properties.

 To find out more about this research, read the Chemical Science Edge article.

Scientists have found that the way ice bonds to metal does not obey the ‘ice rules’. Andrew Hodgson, together with teams from the UK and Spain, wanted to understand water–metal and hydroxyl–metal interactions, to devise molecular models of wet metal interfaces for studying catalytic and electrochemical reactions that occur on these types of surfaces.

Using scanning tunnelling microscopy and density functional theory calculations, the teams produced a phase diagram for water and hydroxyl on a copper surface, providing a complete molecular description of the complex hydrogen bonding structures formed. They saw three distinct phases as the temperature was decreased and the water/hydroxyl ratio increased: pure OH dimers, extended 1H₂O:1OH chains aligned along the close-packed Cu rows, and finally a distorted 2D hexagonal c(2 × 2) 2H₂O:1OH network.

Binding geometry and simulated STM images for (a) an isolated OH group, (b) an OH dimer and (c) an array of OH forming a dimer chain on the copper surface

None of these phases obey the conventional ‘ice rules’. Instead, their structures can be understood based on weak H donation by hydroxyl, which favours H-bonding structures dominated by water donation to hydroxyl, and competition between hydroxyl adsorption sites.

Found out more by downloading the Chemical Science Edge article.

A method for making modified RNA provides a new tool to study non-coding RNAs (functional RNA molecules not translated into a protein), say researchers from Germany and Austria.

Chemical synthesis of modified DNA and RNA is limited by size and by type of modification, so scientists are searching for new methods to overcome these limitations. To modify RNA, Ronald Micura and Andreas Marx and their teams used an enzyme – an RNA polymerase – rather than conventional synthesis methods.

To find out more, read the Edge article.

Researchers have shown that acid-catalysed condensations of aminobenzaldehydes with indole result in the formation of different products depending on whether the aminobenzaldehyde is primary or secondary.

Daniel Seidel’s group at Rutgers, The State University of New Jersey, found that N-methylbenzaldehyde reacts with indole to form neocryptolepine-related structures in a single step. Neocryptolepine (5) and its analogues are attractive targets for synthesis as they display promising antimalarial activity.

Conversely, primary benzaldehydes such as aminobenzaldehyde react under similar conditions to form quinolines (7). The mechanistic pathways leading to the formation of both indoles (5) and quinolines (7) are initially identical, with aminobenzaldehyde 1 condensing with indole 2 to form the corresponding azafulvenium ions (3), which undergo ring closure to yield tetracyclic products (4). At this point the mechanisms diverge; secondary systems (4a) undergo proton loss and oxidation to give neocryptolepine analogues (5), whilst primary systems (4b) undergo proton transfer to give products of type 6, which aromatise to form quinoline products (7) on ring opening.

The group made a range of both neocryptolepine analogues and quinoline systems in good to excellent yields, representing important scaffolds for medicinal chemistry.

Seidel’s Edge article is free to download. Let me know what you think of this work by leaving your comments below.

Posted on behalf of Alice E. Williamson, Chemical Science web writer.

Researchers from the University of Delaware have reported a total synthesis of hyacinthacine A2, an attractive target owing to its selective glycosidase inhibition and activity against HIV. 

Joseph Fox’s research group achieved the synthesis in less than ten steps from sucrose by designing and synthesising a functionalised 5-aza-cyclooctene system (1) that would undergo a novel transannular hydroamination, following stereocontrolled photoisomerisation.

The efficiency of the photoisomerisation process was improved by using a flow system that removes trans-isomers by selective complexation with silver salts, thereby enabling the cis-isomer of 1 to be recycled. Incorporation of a fused acetonide ring system in 1 imposed significant conformational constraints to favour formation of the desired trans-diastereosiomer 2 in good yield and in 8:1 diastereomeric ration following decomplexation from the silver salts.

Following separation of the major diasteroisomer of 2, and cleavage of both trifluoroacetyl and acetonide protecting groups, the corresponding ammonium salt was obtained. The planar chirality present in 2 was perfectly transferred in a transannular hydroamination to give the point chirality present in the natural product.

Find out more by downloading Professor Fox’s Chemical Science Edge article, which is free to access.

Posted on behalf of Alice E. Williamson, Chemical Science web writer.