Biogenic amines play key roles in neurotransmission, metabolism, and in control of various physiological processes. Using a variety of synthetic methodologies, including novel procedures developed by us, we initially prepared in racemic form a series of biogenic amines with fluorine substituted at various ring-positions. These ring-fluorinated biogenic amines continue to find applications in a multitude of studies, including research on the mechanisms of transport, storage, release, metabolism, and modes of action of these amines. Of particular significance was the discovery that 6-fluoronorepinephrine (6-FNE) is a selective alpha-adrenergic agonist and 2-fluoronorepinephrine (2-FNE) is a selective beta-adrenergic agonist. This behavior also was seen with fluorinated epinephrines (FEPI) and other phenethanolamine agonists. In a recent extension of this work we prepared the R- and S-enantiomers of 2- and 6-FNE and the R- and S-enantiomers of 2- and 6-FEPI. In order to have available alternate biological precursors for R-2-FNE and R-6-FNE, we also prepared the 2S,3R-isomers of 2- and 6-fluoro-dihydroxyphenylserine (2F- and 6F-L-threo-DOPS), first using Evans enantioselective aldol strategy, and more recently using an efficient Sharpless asymmetric aminohydroxylation procedures. Aromatic amino acid decarboxylase converts 6-F-L-threo-DOPS to R-6-FNE, but a competing Pictet Spengler cyclization with the pyridoxal phosphate cofactor diminishes the efficiency of the process. With 2F-L-threo-DOPS, the Pictet Spengler reaction predominates and decarboxylation is essentially blocked. Prompted by this observation, we initiated enantioselective syntheses of 2-F-, 5-F-, 6-F-, and 2,6-diF-L-DOPA in order to study the effects of ring-fluorination on the rate of enzymatic decarboxylation of these analogues. [18F]6F-L-DOPA has been used extensively in PET studies to quantify dopaminergic function, and rates of decarboxylation are thus important considerations. Initial results indicate that 6-F-L-DOPA is a very effective substrate, and is decarboxylated more rapidly than L-DOPA. Ring-fluorinated imidazoles we previously prepared also have been very valuable as biochemical and pharmacological agents. We now have developed syntheses of side-chain fluorinated biologically important imidazoles, including beta-fluoro- and beta,beta-difluorohistamine, and beta-fluorourocanic acid. We are extending this to the corresponding histidine derivatives, and biosynthetic precursors of histidine. Fluorinated cis-urocanic acids are being used to study the mechanism of cis-urocanic acid-mediated photo-immunosuprression. Several inhibitors, some medicinally effective, of the important metabolic enzyme, monoamine oxidase (MAO), contain fluorine as an important feature that is critical to the inhibitory mechanism. Other inhibitors contain cyclopropane for the same purpose. We have prepared and are now studying a series of benzylamines and phenylethylamines that incorporate fluorinated cyclopropyl groups in the side chain as new MAO inhibitors to determine the combined effects of these two structural motifs.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Intramural Research (Z01)
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Hajduch, Jan; Cramer, John C; Kirk, Kenneth L (2008) An Enantioselective Synthesis of (S)-4-Fluorohistidine. J Fluor Chem 129:807-810
Hajduch, Jan; Dolensky, Bohumil; Yoshida, Shinichi et al. (2008) Synthesis of (E)- and (Z)-alpha,beta-Difluorourocanic Acid. J Fluor Chem 129:112-118
Fujiwara, Tomoya; Yin, Bin; Jin, Meixiang et al. (2008) Synthetic Studies of 3-(3-Fluorooxindol-3-yl)-l-alanine. J Fluor Chem 129:829-835
Hajduch, Jan; Nam, Ghilsoo; Kim, Eun Ju et al. (2008) A convenient synthesis of the C-1-phosphonate analogue of UDP-GlcNAc and its evaluation as an inhibitor of O-linked GlcNAc transferase (OGT). Carbohydr Res 343:189-95
Heredia-Moya, Jorge; Kirk, Kenneth L (2007) Photochemical Schiemann Reaction in Ionic Liquids. J Fluor Chem 128:674-678
Wimalasena, D Shyamali; Cramer, John C; Janowiak, Blythe E et al. (2007) Effect of 2-fluorohistidine labeling of the anthrax protective antigen on stability, pore formation, and translocation. Biochemistry 46:14928-36
Nagasawa, Hideko; Uto, Yoshihiro; Kirk, Kenneth Lee et al. (2006) Design of hypoxia-targeting drugs as new cancer chemotherapeutics. Biol Pharm Bull 29:2335-42
Uto, Yoshihiro; Ae, Shutaro; Koyama, Daisuke et al. (2006) Artepillin C isoprenomics: design and synthesis of artepillin C isoprene analogues as lipid peroxidation inhibitor having low mitochondrial toxicity. Bioorg Med Chem 14:5721-8
Kirk, Kenneth L (2006) Selective fluorination in drug design and development: an overview of biochemical rationales. Curr Top Med Chem 6:1447-56
Eichler, Jack F; Cramer, John C; Kirk, Kenneth L et al. (2005) Biosynthetic incorporation of fluorohistidine into proteins in E. coli: a new probe of macromolecular structure. Chembiochem 6:2170-3

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