3-Fluoro-D-alanine

A synthetic inhibitor of cell wall synthesis is 3-fluoro-D-alanine which inhibits bacterial growth in competition with D-alanine and exhibits the chemotherapeutic paradox of being more active in vivo than in vitro58. ... 

Bravo, P., Cavicchio, G., Crucianelli, M., et al. (1997) Stereoselective synthesis of the antibacterial 3-fluoro-D-alanine. Tetrahedron Asymmetry, 8, 2811-2815. 

These results indicate that the metabolic disposition and thereby the pharmacological activity, whether efficacious or toxicological, could be modified by selective substitution of deuterium for hydrogen. A new combination antibacterial contains 3-fluoro-D-alanine-2-d which is an excellent example of selective deuteration to enhance the pharmacological activity of a therapeutic agent.7 The metabolism in vivo of 3-fluoro-D-alanine is reduced several-fold by substitution of deuterium for hydrogen on the 2-position without loss of antibacterial activity. This enhances the therapeutic index of the compound because metabolism of 3-fluoro-D-alanine leads to the formation of an inactive antibacterial and fluoride which is nephrotoxic. 

Alanine in position 8 can be successfully substituted for by D-serine to give the corresponding analogs [D-Ser )CyA, (D-Ser JCyB, D-Ser ]CyC, [D-Ser ]CyD, and (o-Ser ]CyG (41). Also, the monohalogcnated 3-fluoro-, 2 deutero-3-fluoro-, and 3-chloro-D-alanines are substrates for competitive in vivo incorporation leading to p-fluoro-D-Ala ]CyA (42), [2-deutero-3 fluoro-D-Ala JCyA (43), and [3-chloro-0-Ala ICyA, respectively. Because the latter amino acids, especially 2 deuterO 3-fluorO D alanine, act as potent inhibitors of alanine racemase (44), the conversion of L-alanine to D-alanine is blocked, and therefore, the biosynthesis of normal CyA is suppressed. 

CFgOF-gas passed ca. 19 hrs. under dry Ng at -78° into a vigorously stirred soln. of D-alanine in liq. HF irradiated with the quartz-filtered light of a 1000 w. Hg-Xe-lamp 3-fluoro-D-alanine. Y 57%. Also L-isomer s. J. Kollonitsch and L. Barash, Am. Soc. 98, 5591 (1976). 

In an extension of this work, it was found that 3-fluoro-D-alanine is highly effective in vivo against all the commoner Gram-positive and -negative infections, and is antagonised by D-alanine (see further Section... 

Adamantanc is fluorinated by trifluoromethyl hypofluorite with the highest yields being obtained in the presence of radical inhibitors (see Vol. ElOa. p 270ff). This is in sharp contrast to reported photo-induced monofluorinaiions of cyclohexane and amino acids with tri-fluoroniethyl hypofluorite, which do not proceed in the absence of light.An example is the fluorination of o-alanine to give 3-fluoro-D-alunine (3). "... 

Fluoro-D-[2- H] alanine (20) shows the same antibacterial activity as the protio form of the fluoroamino acid. However, since the metabolism in vivo is several fold less substitution of the deuterium produces enhanced pharmacological activity [167],... 

A related procedure is seen at work in an anti-bacterial IMBI, D-3-fluoro-alanine (9.91), which is being clinically studied. This substance irreversibly inhibits alanine racemase, the enzyme that provides essential D-alanine for synthesizing the walls of bacteria (Wang and Walsh, 1978). 

D,L-Fluorophenylalanine DL-3-(p-Fluorophenyl) alanine DL-4-Fluorophenylalanine DL-p-Fluorophenylalanine p-Fluoro-D,L-phenylalanine FPA Empirical C9H10FNO2 Formula FC6H4CH2CH(NH2)C02H Properties Wh. powd. or shiny flakes sol. < 1 mg/ml in water, DMSO, 95% ethanol, acetone m.w. 183.18 m.p. 253-255 C (dec.)... 

D. J. Sweeney, S. Barnes, R. B. Diasio, Formation of Conjugates of 2-Fluoro-/3-alanine and Bile Acids during the Metabolism of 5-Fluorouracil and 5-Fluoro-2-deoxyuridine in the Isolated Perfused Liver , Cancer Res. 1988, 48, 2010-2014. 

Fluoro-2,4-dinitrophenyl-5-L-alanine amide (Marfey s reagent) and 2..3.4.6-tetra-0-aeetyl-P-D-gluer>pyranosyl isothkKyanatc... 

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