<b>A Stereospecific Synthesis of D(-)-Shikimic Acid</b>

Smissman, Edward E.; Suh, John T.; Oxman, Michael A.; Daniels, Ralph

doi:10.1021/ja00865a034

Cited by 46 publications

(12 citation statements)

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“…Because of the similar structures and conformations of 7 and 12, it is difficult to rationalize their large difference in activity if they inactivate GABA-AT through the same inactivation pathway. Elimination of the fluoride ion from 12 leads to an intermediate (22), which is the protonated form of an intermediate proposed in the aromatization mechanism by gabaculine 14 (25, Schemes 4 and 5) and produces the identical product as that from gabaculine inactivation (26).…”

Section: Mechanism Of Inactivation Of Gaba-at By 12mentioning

confidence: 99%

(±)-(1S,2R,5S)-5-Amino-2-fluorocyclohex-3-enecarboxylic Acid. A Potent GABA Aminotransferase Inactivator that Irreversibly Inhibits via an Elimination−Aromatization Pathway

et al. 2006

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Inhibition of γ-aminobutyric acid aminotransferase (GABA-AT) raises the concentration of GABA, an inhibitory neurotransmitter in human brain, which could have therapeutic applications for a variety of neurological diseases including epilepsy. Based on studies of several previously synthesized conformationally-restricted GABA-AT inhibitors, (±)-(1S,2R,5S)-5-amino-2-fluorocyclohex-3-ene carboxylic acid (12) was designed as a mechanismbased inactivator. This compound was shown to irreversibly inhibit GABA-AT; substrate protects the enzyme from inactivation. Mechanistic experiments demonstrated the loss of one fluoride ion per active site during inactivation and the formation of N-m-carboxyphenylpyridoxamine 5′-phosphate (26), the same product generated by inactivation of GABA-AT by gabaculine (8). An elimination-aromatization mechanism is proposed to account for these results.γ-Aminobutyric acid aminotransferase (GABA-AT, E.C. 2.6.1.19) is the enzyme responsible for the degradation of γ-Aminobutyric acid (GABA), one of the major inhibitory neurotransmitters in the mammalian central nervous system, 1 to succinic semialdehyde. Inhibition of this enzyme results in an increased concentration of GABA in the brain and could have therapeutic applications in neurological disorders including epilepsy, 2 Parkinson's disease, 3 Huntington's chorea, 4 and Alzheimer' disease. 5 In fact, vigabatrin (1 , Figure 1), an irreversible inactivator of GABA-AT, is a drug for the treatment of epilepsy. 6 It has also been found that an increase in the availability of GABA blocks the effects of drug addiction. 7We recently reported several fluorine-containing conformationally-restricted analogues of GABA ( Figure 1, 2-4) as potential meschanism-based inactivators 8 of GABA-AT, but they turned out to have only minimal reversible inhibitory activity; the non-fluorinated parent compound also was devoid of substrate or inhibitory activity. 9 However, the corresponding † The authors are grateful to the National Institutes of Health (GM66132) for financial support of this research. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript cyclopentane analogue of 2, namely 5, was shown to be a time-dependent inactivator of GABA-AT; 10 it inactivates the enzyme by an enamine mechanism. 11 Likewise, (1R,4S)-(+)-4-amino-2-cyclopentene-1-carboxylic acid (6) is a substrate and inhibitor of GABA-AT but not an inactivator, 12 whereas, the corresponding cyclohexene analogue (7) is a time-dependent inactivator of GABA-AT, which also was demonstrated to inactivate the enzyme by an enamine mechanism, in this case leading to a ternary complex between the enzyme, the PLP cofactor, and 7. 13 It was reasoned that the flexible chair conformation of the cyclohexane ring is responsible for the inability of these compounds to inactivate the enzyme, and that the more rigid structures of the corresponding cyclopentane or cyclohexene analogues are more effective inactivators. This also is consistent with the observation that the natural produ...

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Section: Mechanism Of Inactivation Of Gaba-at By 12mentioning

confidence: 99%

(±)-(1S,2R,5S)-5-Amino-2-fluorocyclohex-3-enecarboxylic Acid. A Potent GABA Aminotransferase Inactivator that Irreversibly Inhibits via an Elimination−Aromatization Pathway

et al. 2006

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“…Chemical syntheses of ['"CI-labelled shikimic acid have been described but suffered from a low yield of the natural D-enantiomer (2, 8).…”

Section: Introductionmentioning

confidence: 99%

Facile and economical preparation of [¹⁴C]‐labelled shikimic acid

Krüper

Gehrke

Amrhein

1990

Labelled Comp Radiopharmac

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SummaryA convenient and inexpensive method for the preparation of ["CC]-labelled shikirnic acid based on the photoassimilation of "CO, by henbane (ffyoscyamus niger L.) leaves in the presence of the herbicide glyphosate is described.Methanolic extracts were purified by successive anion exchange, paper and thin-layer chromatography to yield ["C]-labelled shikimic acid of 99.5% radiochemical purity, as shown by analytical HPLC. Under the conditions employed, the rate of incorporation of 14C0, into shikimic acid (0.7 -17.6%) showed a positive correlation with the size of the leaf used in the incubation (3.6 -146 mg fresh weight), while the specific activity of the acid (6 -12.7 GBq/mmol) was an inverse function of the leaf size.

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“…Les carbones 2 et 3 de l'acrylate de mCthyle se retrouvent en positions 1 et 2 sur le cycle de l'acide shikimique (I) l. Nous avions mis au point antkrieurement [6] la synthbse de l'acrylate de mtthyle 14C-2-3. La cishydroxylation de la double liaison du diacttoxy 2p-5p cyclohexbne-3 carboxylate-1 tc de mCthyle (IV) en position anti par rapport aux groupes acetoxy a Ct C obtenue par action du tetroxyde d'osmium en presence de pyridine selon une simplification de la technique de [4]. Les deux hydroxyles en cis de (V) sont proteges par le groupe isopropylidkne.…”

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“…Les deux hydroxyles en cis de (V) sont proteges par le groupe isopropylidkne. Pour ce faire, la technique de SMMISSMAN [4] : acetone anhydre en presence d'acide chlorhydrique nous a donne un rendenient trop faible (45 % environ). En manipulant l'acetone sur rampe B vide, B l'etat gazeux nous avons pu porter a 66 % le rendement en acktonide (VI).…”

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Synthèse de l'acide DL‐shikimique ¹⁴C‐1–2 à partir de l'acrylate de méthyle ¹⁴C‐2–3

Chabannes

Pichat²,

Herbert³

et al. 1965

J. Labelled Cpd. Radiopharm.

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SUMMARY DL-L'acide shikimique (I), trbs repandu dans le rkgne vegetal, est un precurseur du noyau phhyle de differentes molCcules, en particulier du noyau C des composes flavoniques ; plusieurs unites C,-C, (phknylalanine -acide cinnamique -acide phenylpyruvique) peuvent aussi &re incorporees dans les composes flavoniques mais leur pourcentage d'incorporation est plus faible que celui de l'acide shikimique [la]. Afin de preciser chez les vkgetaux, d'une part les Ctapes qui se situent entre l'acide shikimique et ces unites C,-C,, d'autre part, la filiation des composes flavoniques, nous avons entrepris la synthbse de ce produit marque au 14C dans le noyau cyclohexknique.

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A Stereospecific Synthesis of D(-)-Shikimic Acid

Cited by 46 publications

References 1 publication

(±)-(1S,2R,5S)-5-Amino-2-fluorocyclohex-3-enecarboxylic Acid. A Potent GABA Aminotransferase Inactivator that Irreversibly Inhibits via an Elimination−Aromatization Pathway

(±)-(1S,2R,5S)-5-Amino-2-fluorocyclohex-3-enecarboxylic Acid. A Potent GABA Aminotransferase Inactivator that Irreversibly Inhibits via an Elimination−Aromatization Pathway

Facile and economical preparation of [¹⁴C]‐labelled shikimic acid

Synthèse de l'acide DL‐shikimique ¹⁴C‐1–2 à partir de l'acrylate de méthyle ¹⁴C‐2–3

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A Stereospecific Synthesis of D(-)-Shikimic Acid

Cited by 46 publications

References 1 publication

(±)-(1S,2R,5S)-5-Amino-2-fluorocyclohex-3-enecarboxylic Acid. A Potent GABA Aminotransferase Inactivator that Irreversibly Inhibits via an Elimination−Aromatization Pathway

(±)-(1S,2R,5S)-5-Amino-2-fluorocyclohex-3-enecarboxylic Acid. A Potent GABA Aminotransferase Inactivator that Irreversibly Inhibits via an Elimination−Aromatization Pathway

Facile and economical preparation of [14C]‐labelled shikimic acid

Synthèse de l'acide DL‐shikimique 14C‐1–2 à partir de l'acrylate de méthyle 14C‐2–3

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Facile and economical preparation of [¹⁴C]‐labelled shikimic acid

Synthèse de l'acide DL‐shikimique ¹⁴C‐1–2 à partir de l'acrylate de méthyle ¹⁴C‐2–3