Activity-directed synthesis of bioactive small molecules


Contact Professor Adam Nelson to discuss this project further informally.

Project description

The functional and structural diversity of natural products continues to inspire drug discovery and chemical biology. Natural products arise through the evolution of biosynthetic pathways, driven by functional benefit to the host organism. In stark contrast, most other bioactive molecules are discovered through optimisation rounds in which synthesis, purification and assaying are distinct activities.

To expedite discovery, a narrow toolkit of reliable methods has emerged, tending to focus attention on a limited range of molecular scaffolds. Current discovery paradigms thus tend to discourage exploitation of the full power of modern synthetic methods. We have recently described a new discovery approach – which we term activity-directed synthesis (ADS) – in which novel bioactive small molecules emerge in parallel with associated syntheses. Distinctively, ADS harnesses the promiscuity of reactions that can yield alternative products. Although such reactions explore diverse chemical space, they are rarely exploited in current discovery approaches which generally require high-yielding reactions with predictable products. In each round of ADS, a reaction array is performed with outcomes that are critically dependent on the specific substrates/catalysts/conditions used. To steer reactions towards bioactive products, subsequent arrays are informed by the bioactivity of the product mixtures. Finally, reactions that yield highly active product mixtures are scaled up to reveal, after purification, the responsible bioactive structures. Thereby, ADS can enable adventurous and powerful synthetic methods to be exploited in the discovery of bioactive molecules in parallel with associated syntheses.

The project will involve the expansion of the platform of chemical reactions that are configured for ADS, and the exploitation of ADS in the discovery of novel and diverse small molecules with specific biological functions.

Entry requirements

Applications are invited from candidates with or expecting a minimum of a UK upper second class honours degree (2:1), and/or a Master's degree in chemistry or chemical biology or another relevant discipline.

How to apply

If English is not your first language, you must provide evidence that you meet the University’s minimum English Language requirements.

Formal applications for research degree study should be made online through the university's website. Please state clearly in the research information section that the PhD you wish to be considered for is the 'Activity-directed synthesis of bioactive small molecules’ as well as Professor Adam Nelson as your proposed supervisor.

If you require any further information please contact the Graduate School Office

We welcome scholarship applications from all suitably-qualified candidates, but UK black and minority ethnic (BME) researchers are currently under-represented in our Postgraduate Research community, and we would therefore particularly encourage applications from UK BME candidates.  All scholarships will be awarded on the basis of merit.