Activity-directed synthesis of bioactive small molecules

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.

<p>The earliest start date for this project is 1 October 2020.</p>

<p>Formal applications for research degree study should be made online through the&nbsp;<a href="https://www.leeds.ac.uk/info/130206/applying/91/applying_for_research_degrees">University&#39;s website</a>. Please state clearly in the research information section&nbsp;that the research degree you wish to be considered for is &lsquo;Activity-directed synthesis of bioactive small molecules&rsquo;&nbsp;as well as&nbsp;<a href="https://physicalsciences.leeds.ac.uk/staff/180/professor-adam-nelson">Professor Adam Nelson</a>&nbsp;as your proposed supervisor.</p> <p>If English is not your first language, you must provide evidence that you meet the University&#39;s minimum English language requirements (below).</p> <p><em>We welcome 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.</em></p>

Applicants to research degree programmes should normally have at least a first class or an upper second class British Bachelors Honours degree (or equivalent) in an appropriate discipline. The criteria for entry for some research degrees may be higher, for example, several faculties, also require a Masters degree. Applicants are advised to check with the relevant School prior to making an application. Applicants who are uncertain about the requirements for a particular research degree are advised to contact the School or Graduate School prior to making an application.

The minimum English language entry requirement for research postgraduate research study is an IELTS of 6.0 overall with at least 5.5 in each component (reading, writing, listening and speaking) or equivalent. The test must be dated within two years of the start date of the course in order to be valid. Some schools and faculties have a higher requirement.

<p><strong>Self-Funding Students</strong></p> <p><strong>Funding Eligibility</strong></p> <p><strong>UK/EU</strong> &ndash;&nbsp;Leeds Doctoral Scholarship Award paying Academic Fees and Maintenance matching EPSRC rate of &pound;15,009 per year for 3 years, Lowson Research Scholarship &amp; John Henry Garner paying Academic Fees and Maintenance at a fixed rate of &pound;14,000 per year for 3 years, School of Chemistry Scholarship award paying Academic Fees and Maintenance matching EPSRC rate of &pound;15,009 per year for 3 years.&nbsp; Alumni Bursary is available to previous University of Leeds graduates offering 10% discount on Academic Fees.</p> <p><strong>International Students</strong> &ndash;&nbsp;China Scholarship Council-University of Leeds Scholarship Award paying Academic Fees for 3 years,&nbsp;School of Chemistry Scholarship award paying Academic Fees for 3 years, Commonwealth Scholarship and Commonwealth Split Site Scholarships.&nbsp; Alumni Bursary is available to previous University of Leeds graduates offering 10% discount on Academic Fees.</p>

<p>For further information regarding your application, please contact Doctoral College Admissions by&nbsp;email: <a href="mailto:maps.pgr.admissions@leeds.ac.uk">maps.pgr.admissions</a><a href="mailto:EMAIL@leeds.ac.uk">@leeds.ac.uk</a>, or by telephone: +44 (0)113 343 5057.</p> <p>For further information regarding the project, please contact Professor Adam Nelson by email:&nbsp;&nbsp;<a href="mailto:A.S.Nelson@leeds.ac.uk">A.S.Nelson@leeds.ac.uk</a></p>