Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Patent
1993-12-27
1996-05-14
Dees, Jose G.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
562 11, 562443, C07C32124, A61K 31195
Patent
active
055169368
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
Kynureninases are a group of pyridoxal-5'-phosphate dependent enzymes which catalyze the hydrolyric .beta.,.gamma.-cleavage of aryl-substituted .alpha.-amino-.gamma.-keto acids, particularly L-kynurenine or 3-hydroxy-L-kynurenine to give L-alanine and anthranilic acid or 3-hydroxyanthranilic acid, respectively (see: K. Soda and K. Tanizawa (1979)Advances Enzym. 49:1-40). Kynureninase is involved in the microbial catabolism of L-tryptophan via the aromatic pathway. In plants and animals, a kynureninase is required in tryptophan catabolism and for NAD biosynthesis via guinolinic acid. Quinolinic acid is a relatively toxic metabolite which has been implicated in the etiology of neurological disorders, including epilepsy and Huntington's chorea (R. Schwarcz et al. (1988) Proc. Natl. Acad. Sci. USA 85:4079; M. F. Beal et al. (1986) Nature 321:168-171; S. Mazzari et al. (1986) Brain Research 380:309-316; H. Baran and R. Schwarcz (1990) J. Neurochem. 55:738-744). Inhibitors of kynureninase are thus important targets for treatment of such neurological disorders.
L-kynurenine (which can also be designated .alpha.,2-diamino-.gamma.-oxobenzenebutanoic acid) is the preferred substrate of bacterial kynureninase, which is exemplified by that of Pseudomonas fluorescens (O. Hayaishi and R. Y. Stanier (1952) J. Biol. Chem. 195:735-740). The kynureninase of tryptophan metabolism in plants and animals has a somewhat different substrate specificity with 3-hydroxy-L-kynurenine (which can be designated .alpha.,2-diamino-3-hydroxy-.gamma.-oxobenzenebutanoic acid) being the preferred substrate (Soda and Tanizawa (1979) supra).
The mechanism of kynureninases has been the subject of considerable interest due to the unique nature of this pyridoxal-5'-phosphate dependent reaction. Mechanisms based on redox reactions (J. B. Longsnecker and E. E. Snell (1955) J. Biol. Chem. 213:229-235) or transamination (C. E. Dalgleish et al. (1951) Nature168:20-22) have been proposed. More recently mechanisms involving either a nucleophilic mechanism with an "acyl-enzyme" intermediate (C. Walsh (1979) "Enzymatic Reaction Mechanisms" W. H. Freeman and Co., San Francisco, p. 821; M. Akhtar et al. (1984) "The Chemistry of Enzyme Action" New Comprehensive Biochemistry, Vol. 6 (M. I. Page, ed.) Elsevier, New York, p.821) or a general base-catalyzed mechanism (K. Tanizawa and K. Soda (1979) J. Biochem. (Tokyo) 86:1199-1209) have been proposed.
In addition to the physiological reaction, kynureninase has been shown to catalyze an aldol-type condensation of benzaldehyde with incipient L-alanine formed from L-kynurenine to give .alpha.-amino-.gamma.-hydroxy-.gamma.-phenylbutanoic acid (G. S. Bild and J. C. Morris (1984) Arch. Biochem. Biophys. 235:41-47). The stereochemistry of the product at the .gamma.-position was not determined, although the authors suggested that only a single isomer was formed.
J. L. Stevens (1985) J. Biol. Chem 260:7945-7950 reports that rat liver kynureninase displays cysteine conjugate .beta.-lyase activity. This enzyme activity is associated with cleavage of s-cysteine conjugates of certain xenobiotics to give pyruvate, ammonia and a thiol, for example, cleavage of S-2-(benzothiazolyl)-L-cysteine to give 2-mercaptobenzothiazole, pyruvate and ammonia. More recently, I. S. Blagbrough et al. (1990) Toxicol. Lett 53(1-2):257-259 (Chem. Abstract 114(9):77537k) report that cysteine conjugate .beta.-lyase (C-S-lyase) is a member of a family of transaminases and aminotransferases and that C-S lyase is a glutamine transaminase K. The reference discusses structure-activity relations displayed by C-S-lyases. C-S-lyases are distinguishable from kynureninase but exhibit overlapping activities.
Several reports concerning the relative reactivities of kynurenine analogs with bacterial kynureninase or rat liver kynureninase are summarized in Soda and Tanizawa (1979) supra. Tanizawa and Soda (1979) supra reported that a number of ring substituted L-kynurenines, namely: 3-hydroxy-, 5-hydroxy-, 5-methyl-, 4-fluoro-, and 5-f
REFERENCES:
patent: 4293569 (1981-10-01), Haugwitz et al.
patent: 4332813 (1982-06-01), Firestone
patent: 4609673 (1986-09-01), Eggerer et al.
patent: 4730008 (1988-03-01), Skidmore et al.
patent: 5254725 (1993-10-01), Phillips et al.
Dua et al. (1992) Abstract entitled "S-Aryl-L-Cysteine Sulfone: A New Class of Mechanism Based Inhibitors of Kynureninase," Abstracts, Amer. Chem. Soc. vol. 203 (Apr.), 119 (MEDI).
Phillips & Dua (1991), "Stereochemistry and Mechanism of Aldol Reactions Catalyzed by Kynureninase", Abstracts, Amer. Chem. Soc. vol. 201 (Apr.) 283 (ORGN).
Phillips & Dua (1991), "Stereochemistry and Mechanism of Aldol Reactions Catalyzed by Kynureninase", J. Amer. Chem. Soc. 113:7385-7388.
Kibat et al. (1990), "Enzymatically Activated Microencapsulated Liposomes can Provide Pulsatile Drug Release", The FASEB Journal, 4:2533-2539.
Crescenzi et al. (1990), "Synthesis and Reactivity of Cyclic Quinonimines of the 2H-1, 4-Benzothiazine Series", Gazetta Chimica Italiana 120:21-24.
J. P. Whitten et al. (1989), "A Convenient Synthetic Access to .beta., .beta.-Difluoro-.alpha.-Amino Acids. Application to the Synthesis of a Potential Inhibitor of Kynureninase", Tetrahedon Letters 30:3649-3652.
Blagbrough et al. (1988), "Inhibition of Rat Renal C-S Lyase: Assessment Using Kidney Slice Methodology," Drug Metab. Drug Interact 6:(3-4) 303-316.
Blagbrough et al. (1988), "Substrates for Rat Renal C-S Lyase," J. Pharm. Pharmacol. 41(suppl.): 148.
Vamvakas et al. (1988), "Bacterial cysteine Conjugate .beta.-Lyase and the Metabolism of Cysteine S-Conjugates: Structural Requirements for the Cleavage of S-Conjugates and the Formation of Reactive Intermediates", Chem. Biol. Interact 65:59-71.
Tarzia et al. (1988) "Alkyl 2-(Diphenylmethyleneamino) Acrylates in the Synthesis of .alpha.-Amino Acids", Synthesis 7:514-517.
J. L. Stevens (1985), "Isolation and Characterization of a Rat Liver Enzyme with Both Cysteine Conjugate .beta.-Lyase and Kynureninase Activity", J. Biol. Chem 260:7945-7950.
Palcic et al. (1985), "Stereochemistry of the Kynureninase Reaction", J. Biol. Chem. 260:5248-5251.
G. A. Flynn et al. (1984), Tettrahedon Lett. 25:2655-2658.
G. M. Kishore (1984), "Mechanism-based Inactivation of Bacterial Kynureninase by .beta.-Substituted Amino Acids", J. Biol. Chem. 259:10669-10674.
K. Tanizawa et al. (1979), "The Mechanism of Kynurenine Hydrolysis Catalyzed by Kynureninase", J. Biochem. 86:1199-1209.
K. Soda and K. Tanizawa (1979), "Kynureninase: Enzymological Properties and Regulation Mechanism", Advances Enzym. 49:1-40.
F. McCapra and Z. Razavi (1976), "Biosynthesis of Luciferin in Pyrophorus Pellucens", J. Chem. Soc. 5:153-154.
T. L. Gilchrist et al. (1979), "Ethyl 3-Bromo-2-hydroxyiminopropanoate, a Reagent for the Preparation of Ethyl Esters of .alpha.-Amino Acids", J.C.S. Chem. Comm. 1089-1090.
A. P. Damoglou et al. (1971), "The Hydrolysis by Thermolysin of Dipeptide Derivatives that Contain Substituted Cysteine", Biochem. J. 123:379-384.
Mikheeva et al. (1968) Chem. Abstracts 69:18764m.
Tolosa et al. (1968) Chem. Abstracts 70(1):482d and English Abstract of Tolosa et al. (1968) Mol. Biol. 2(5):769-777 (in Russian).
L. Goodman et al. (1958), "Potential Anticancer Agents v. Some Sulfur-Substituted Derivatives of Cysteine", J. Org. Chem. 23:1251-1257.
O. Hayaishi (1955) in "A Symposium on Amino Acid Metabolism" (W. D. McElroy and H. B. Glass, eds.) Johns Hopkins Press, Baltimore pp. 914-929.
O. Wiss and H. Fuchs (1950) Experientia 6:472-473.
Dua Rajesh K.
Phillips Robert S.
Dees Jos,e G.
Frazier Barbara S.
University of Georgia Research Foundation Inc.
LandOfFree
Inhibitors of kynureninase does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Inhibitors of kynureninase, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Inhibitors of kynureninase will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1897106