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Natural organofluorine compounds are rare, with only five examples reliably known out of some 230,000 structurally characterized natural products. The isolation and characterization of a native fluorination enzyme by David O’Hagan of the University of St Andrews, in Scotland, and his colleagues has thus given chemists insight into how to take advantage of this rare fluorine biochemistry. O’Hagan’s discovery is considered a milestone achievement in fluorine chemistry because of the growing importance of strategic placement of fluorine in molecules to improve the bioavailability and efficacy of drugs.
“O’Hagan literally put fluorine into the vocabulary of biosynthesis,” says organofluorine chemist Gerald B. Hammond of the University of Louisville.
In 2002, O’Hagan and his colleagues isolated the fluorinase enzyme from the soil bacterium Streptomyces cattleya. They determined that the enzyme evolved to catalyze formation of a C–F bond using fluoride ion. The initial fluorinated product in the microbe’s biosynthetic pathway is 5′-fluoro-5′-deoxyadenosine, which is then converted by other enzymes to 4-fluorothreonine and fluoroacetate (FCH2CO2–), the latter of which is the most ubiquitous of the known natural organofluorine compounds.
In 2010, O’Hagan and his collaborators coaxed the deep-sea sediment microbe Salinospora tropica to accept the fluorinase gene in place of a chlorinase gene. The researchers put the engineered microbe to work making a fluorinated version of the anticancer drug candidate salinosporamide A. This achievement is the first step toward practical fermentation production of fluorinated drugs.
Intermediates in the fluorinase-mediated pathway, including fluorosugars, have the potential to be shunted off in different directions to make a variety of fluorochemicals, O’Hagan says. For example, his team is using the enzyme to prepare [18F]-fluorodeoxyribose as a new radiotracer and bioconjugation ligand for positron emission tomography imaging. Among other fluorine chemistry accomplishments, O’Hagan’s lab has synthesized a family of multiple vicinal fluorine compounds that have potential as organic materials for applications such as liquid crystals.
“His enthusiasm and dedication to the cause of advancing the systematic—rather than the fragmented—knowledge of fluorine chemistry has served as a role model and inspiration to many,” Hammond says.
O’Hagan, 50, is a native of Scotland and received a B.S. in chemistry from the University of Glasgow (1982) and a Ph.D. in chemistry from the University of Southampton, in England (1985). After a postdoctoral research stint at Ohio State University, he joined the faculty at the University of Durham, in England. O’Hagan moved to St Andrews in 2000 and currently is professor and head of organic chemistry.
Among his awards and other honors, O’Hagan is a fellow of the Royal Society of Edinburgh. He received the 2009 Natural Product Reports Lectureship, the 2006 Tilden Lectureship & Medal, and the 2005 Malcolm Campbell Memorial Prize & Medal, all from the Royal Society of Chemistry. He has served on editorial boards of the Journal of Fluorine Chemistry,Bioorganic Chemistry, and Natural Product Reports, and he is an associate editor of the Beilstein Journal of Organic Chemistry. O’Hagan also has been active on committees of the American Chemical Society and the Royal Society of Chemistry.
O’Hagan will present the award address before the ACS Division of Fluorine Chemistry.