Understanding the rules of life

Bioscience for an integrated understanding of health

Category: Standard Studentships

New routes to thiazoles for biological evaluation including bleomycin analogues

Project No. 4265

STANDARD PROJECT

Primary Supervisor

Prof John Spencer – University of Sussex

Co-Supervisor(s)

Dr Matthias Baud – University of Southampton

Dr Storm Hassell-Hart- University of Sussex

Summary

Atom-economical methodologies enable access to novel chemical entities for biological testing

1. Atom-economical methodologies enable access to novel chemical entities for biological testing. In this respect, our iridium-catalysed synthesis of thiazoles with antibacterial properties (Org Lett 2022, see below) is a breakthrough in the synthesis of this class of heterocycles, since it overcomes many shortfalls of traditional Hantzsch chemistry, displaying high functional group tolerance and mild reaction conditions. We will extend this chemistry towards bis-thiazoles, including analogues of the anticancer agent bleomycin at Sussex (JS, SHH) and biophysical testing at Southampton (Baud). We will develop a thiazole library synthesis using parallel, robotic, synthetic methods in order to produce 100s of new entities. Such methods are transformative since we can save months of manual labour.

2. The student will use automated robotic systems, parallel purification including mass directed HPLC in industry-level laboratories.

3. Impact includes novel libraries, potential IP and/or spin out (JS is a cofounder of Stingray Pharma (kinases in cancer) and non exec director of 113-Botanicals (medical CBD use). Opportunities to test libraries with other collaborators (e.g. INEOS Centre, Oxford).

4. Candidates with an interest in synthetic and medicinal chemistry with a future ambition of working in the pharmaceutical industry would be ideal for this position. Candidates with a desire to work in a multidisciplinary team, wishing to learn about medicinal, biological and synthetic chemistry  are welcome to apply.

Southampton will profile the properties and bioactivity of the new libraries, focusing on key physico-chemical parameters to assess drug-likeliness (logP, Plasma/Cyp stability, PAINs, etc) and general biomolecular binding capabilities against a panel of in-house targets, using biophysical binding assay cascades (DSF, NMR, ITC, SPR, etc…). The Baud lab have a diverse collection of recombinant high-profile targets in house, such as Wnt signaling effectors, p53 and mutants, and range of cysteine oxi-reductases, with important roles in human and plant biology. Importantly, none of these have validated small molecule ligands, hence the discovery of new molecule binders would be instrumental to uncover their detailed roles in human and plant biology, and possibly their health applications on the longer term.