PhD student Yusra Abdelhamid working in the lab, courtesy Gaunt group
Researchers here have developed a single-step method to synthesise a molecular structure important in drug discovery, which will dramatically speed the search for new drug therapies for pain, neurological disorders and opioid addiction.
Beta-arylethylamine molecules contain an amine separated from an aryl group by two saturated carbon atoms. Small molecules with this unique structure have been shown to have potential to bind with human biological receptors, such as receptors which modulate pain and those which are related to neurological disorders and addiction. A well-known example is dopamine, which binds to a range of human receptors which regulate the reward system, motor activity and memory.
As a result, molecular derivatives with the beta-arylethylamine structure are a key target in drug discovery programmes. The specific spacing of aromatic ring and amine is particularly important in how a molecule might react with receptors. However, until now synthesis of these molecules has involved a time-consuming multi-step process.
Now in research published in Nature, researchers from the Gaunt group describe how they have developed a new catalysis platform that enables beta-arylethylamine derivatives of many shapes and sizes to be assembled in a single step, thereby greatly speeding up the identification and development of potentially useful molecules for developing drug therapies.
“This structure, or motif, is very important in medicine, because it can target a series of diseases,” says first author, Dr Ala Bunescu, who was a postdoctoral researcher in the Gaunt group when she performed the research. “Our new methodology enables researchers to access potentially useful compounds with this structure in a much quicker way. Previous methods needed four or five steps, but this is a one-step method which allows researchers to quickly create and test a series of compounds, and also to build up a library of ‘target’ molecules.”
The single-step catalysis uses two discrete copper catalysts to drive the multi-component coupling of alkenes, aryl-electrophiles and a simple nitrogen-nucleophile. “There are previous reports of dual catalysis but what is really different in our case is that we are using the azide anion in the middle like a bridge to link two separate cycles,” says Bunescu.
The team also demonstrated that by using different metal salts as nucleophiles, the new process is likely to be of use in a number of other pharmaceutically-relevant and wider synthetic applications.
Co-author Yusra Abdelhamid, who is starting her second year as a PhD student in the group,
says she will now be working on developing the chiral form of this reaction, which could lead to another important class of compounds. Abdelhamid already has some promising results. “It’s more challenging than it initially seemed, but as I’ve gained a deeper knowledge of the project and worked on this paper, it’s helped me to develop the work I’m doing now. “
Bunescu, who held a Herchel Smith Fellowship at Cambridge, is now a Junior Professor at the University of Bonn. “I was honoured to hold the Herchel Smith fellowship, which provided such a good opportunity to be a member of the Gaunt group, and was an excellent stepping stone to an academic position.”
As a student funded by the AstraZeneca Cambridge PhD programme, Abdelhamid also has a mentor from AstraZeneca and will have the opportunity for a placement in the medicinal chemistry group there. “During my undergrad studies I didn’t do an industrial placement, so it will give me the chance to have experience in both academia and industry,” she says. She also enjoys working in the Gaunt group. “It’s a large group so there are lots of experts in different areas, and it’s so valuable to be able to go to other postdocs and PhD students in the group who are working on different projects when I need help.”
Matthew Gaunt, who holds the Yusuf Hamied 1702 Chair in Chemistry, says: “It’s been a privilege to work with Ala and Yusra on this project. They’ve developed an exciting new platform for catalytic radical chemistry that is already starting to address long standing problems in this field. We have a lot of new chemistry coming through in this area, and as Yusra says, we are trying really hard to develop a general enantioselective toolkit for this type of radical chemistry.”
Research
A. Bunescu, Y. Abdelhamid, M. Gaunt, Multicomponent alkene azido-arylation by anion-mediated dual catalysis, Accelerated Article Preview, Nature (13 Sept 2021).