Towards efficient and scalable syntheses of fluorinated drug candidates

A major research project in the Linclau group concerns fundamental investigations into how fluorine introduction influences properties such as molecular lipophilicity and hydrogen bond properties of adjacent functional groups. Lipophilicity (logP) is linked to the capacity of compounds to pass cell membranes and is a main parameter in the drug discovery process. The hydrogen bond (H-bond) is the most important specific interaction between a molecule and its local environment, and is of utmost relevance in ligand-protein binding, supra-molecular chemistry, catalysis etc.
A key aim of our research is to apply of our findings in the pharmaceutical arena in order to maximise its impact. In this regard, we have explored a wide range of steroid fluorinations aimed at achieving target selectivity and affinity, based on rational designs guided by our fundamental research. Interestingly, unexpected side-products in the fluorination reactions have also been converted to final targets as an efficient way to increase diversity. This approach has been successful in that a number of Southampton-designed hits have been discovered towards neurodegenerative disease, and a selection will be taken forward to clinical trials by NZP UK.
This CASE project aims the upscaling of a range of such hits. Typically, the synthesis of hits that arose from unexpected side reactions are typically low-yielding and difficult to isolate. The re-synthesis of these hits using the way they were obtained would be very inefficient, and thus require a modified or completely new synthesis. Hence, objective 1 regards the design and optimisation of novel syntheses for a number of these hits. Objective 2 regards the upscaling of these syntheses, which will be carried out on placement.