Dutch scientists have developed a biologically-friendly click reaction which may lead to new tracers for improving the 3D imaging of cancerous tumours.

Click chemistry often includes copper catalysts that remove the need for the high temperatures and pressures. But copper is toxic to most living things so copper-free alternatives are highly sought after.

To achieve this Ben Feringa, University of Gröningen, and his team reacted a benzene ring, substituted with two leaving groups, with various functionalised azides to make benzotriazoles. The reactions could be activated using fluoride salts in combination with a complementary crown ether to give the product in yields of up to 82%. This was achieved in less than two hours without the need for a copper catalyst, or elevated temperatures and pressures.  

Feringa warns that this is just a first step in the right direction for 'developing alternatives to current click chemistry'. 'The problem with the use of this method in the context of living organisms would be that, although it is fast and does not need copper, fluoride is still needed to generate the reactive benzyne and we do not know if it will work in the aqueous environment of a cell.'

David Jackson, Syngenta, Muenchwilen, Switzerland - whose interests include reaction optimisation and clean chemistry - is impressed with the work: 'The benzotriazole unit continues to be of significant interest as a component in new potential new products in the life sciences industry.  The triazole unit is particularly tricky to build at a multi kilogram scale due to the instability of building blocks and reagents. All new mild methods leading to their formation are sure to find applications.'

'With this method in hand our first goal is to introduce radiolabels like fluoride into relevant compounds for positron emission tomography (PET) tracer studies,' says Feringa. 'We are also exploring its use in labelling a range of bioactive compounds where copper-catalysed click reactions are currently used.'

Christina Hodkinson