A convenient chemical-microbial method for developing fluorinated pharmaceuticals

Bright, TV; Dalton, F.; Elder, V.L.; Murphy, C.D.; O’Connor, N.K.; Sandford, G.

Abstract

A significant proportion of pharmaceuticals are fluorinated and selecting the site of fluorine incorporation can be an important beneficial part a drug development process. Here we describe initial experiments aimed at the development of a general method of selecting optimum sites on pro-drug molecules for fluorination, so that metabolic stability may be improved. Several model biphenyl derivatives were transformed by the fungus Cunninghamella elegans and the bacterium Streptomyces griseus, both of which contain cytochromes P450 that mimic oxidation processes in vivo, so that the site of oxidation could be determined. Subsequently, fluorinated biphenyl derivatives were synthesised using appropriate Suzuki–Miyaura coupling reactions, positioning the fluorine atom at the pre-determined site of microbial oxidation; the fluorinated biphenyl derivatives were incubated with the microorganisms and the degree of oxidation assessed. Biphenyl-4-carboxylic acid was transformed completely to 4′-hydroxybiphenyl-4-carboxylic acid by C. elegans but, in contrast, the 4′-fluoro-analogue remained untransformed exemplifying the microbial oxidation – chemical fluorination concept. 2′-Fluoro- and 3′-fluoro-biphenyl-4-carboxylic acid were also transformed, but more slowly than the non-fluorinated biphenyl carboxylic acid derivative. Thus, it is possible to design compounds in an iterative fashion with a longer metabolic half-life by identifying the sites that are most easily oxidised by in vitro methods and subsequent fluorination without recourse to extensive animal studies.

Citation

Bright, T., Dalton, F., Elder, V., Murphy, C., O’Connor, N., & Sandford, G. (2013). A convenient chemical-microbial method for developing fluorinated pharmaceuticals. Organic and Biomolecular Chemistry, 11(7), 1135-1142. https://doi.org/10.1039/c2ob27140k

• Journal Article Type: Article
• Publication Date: Feb 21, 2013
• Deposit Date: May 14, 2013
• Publicly Available Date: May 30, 2014
• Journal: Organic and Biomolecular Chemistry
• Print ISSN: 1477-0520
• Electronic ISSN: 1477-0539
• Publisher: Royal Society of Chemistry
• Peer Reviewed: Peer Reviewed
• Volume: 11
• Issue: 7
• Pages: 1135-1142
• DOI: https://doi.org/10.1039/c2ob27140k
• Public URL: https://durham-repository.worktribe.com/output/1484708