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Novel strategy to introduce fluorine into complex polyketides during biosynthesis

8 August 2022. Over 90 percent of pharmaceutical drugs on the market today are small organic molecules and among those, natural products are highly represented. Fluorination has been widely used in medicinal chemistry for lead structure optimization. About a quarter of all small molecule drugs contain at least one fluorine atom, including the antidepressant Prozac, the cholesterol-lowering drug Lipitor and the quinolone antibiotic Ciprobay. Applications of organofluorine chemistry towards natural product biosynthesis are rare due to the paucity of enzymes that catalyse the addition of F atoms in secondary metabolism. Thus, new methods that enable fluorine derivatization are urgently needed to bridge the gap between the inherent bioactivity of a natural compound and its development as a therapeutic agent.

Polyketide natural products include over 10,000 molecules with a wide range of bioactivities and are among the most prominent classes of approved clinical agents. Modification of polyketides with fluorine offers a promising approach to develop new pharmaceuticals. While synthetic chemical methods for site-selective incorporation of fluorine in complex molecules have improved in recent years, approaches for the biosynthetic incorporation of fluorine in natural compounds are still rare. Scientists from the Buchmann Institute for Molecular Life Sciences at Goethe University Frankfurt, together with colleagues from the University of Michigan, now report a strategy for introducing fluorine into complex polyketides during biosynthesis.

Martin Grininger, Buchmann Institute for Molecular Life Sciences,Institute of Organic Chemistry and Chemical Biology, Goethe University Frankfurt, Frankfurt am Main, Germany,

Rittner A, Joppe M, Schmidt JJ, Mayer LM, Reiners S, Heid E, Herzberg D, Sherman DH, Grininger M (2022) Chemoenzymatic synthesis of fluorinated polyketides. Nature Chemistry, published online 25 July 2022,