2-substituted thiazolidine-4(R)-carboxylic acids as prodrugs of L-cysteine. Protection of mice against acetaminophen hepatotoxicity
A number of 2-alkyl- and 2-aryl-substituted thiazolidine-4(R)-carboxylic acids were evaluated for their protective effect against hepatotoxic deaths produced in mice by LD/sub 90/ doses of acetaminophen. 2(RS)-Methyl-, 2(RS)-n-propyl-, and 2(RS)-n- pentylthiazolidine -4(R)-carboxylic acids (compounds 1b,d,e, respectively) were nearly equipotent in their protective effect based on the number of surviving animals at 48 h as well as by histological criteria. 2(RS)-Ethyl-, 2(RS)-phenyl-, and 2(RS)-(4-pyridyl)thiazolidine-4(R)-carboxylic acids (compounds 1c,f,g) were less protective. The enantiomer of 1b, viz., 2(RS)- methylthiazolidine -4(S)-carboxylic acid (2b), was totally ineffective in this regard. Thiazolidine-4(R)-carboxylic acid (1a), but not its enantiomer, 2a, was a good substrate for a solubilized preparation of rat liver mitochondrial proline oxidase (K/sub m/ 1.1 x 10(-4) M; V/sub max/ . 5.4 mumol min-1 (mg of protein)-1). Compound 1b was not a substrate for proline oxidase but dissociated to L-cysteine in this system. At physiological pH and temperature, the hydrogens on the methyl group of 1b underwent deuterium exchange with solvent D/sub 2/O (k1 . 2.5 X 10(-5) s), suggesting that opening of the thiazolidine ring must have taken place. Indeed, 1b labeled with /sup 14/C in the 2 and methyl positions was rapidly metabolized by the rat to produce /sup 14/CO/sub 2/, 80% of the dose being excreted in this form in the expired air after 24 h. It is suggested that these 2-substituted thiazolidine-4(R)-carboxylic acids are prodrugs of L-cysteine that liberate this sulfhydryl amino acid in vivo by nonenzymatic ring opening, followed by solvolysis.
- Research Organization:
- Medical Research Laboratories, VA Medical Center, Minneapolis, Minnesota
- OSTI ID:
- 7012256
- Journal Information:
- J. Med. Chem.; (United States), Vol. 27:5
- Country of Publication:
- United States
- Language:
- English
Similar Records
PROTECTION AGAINST IONIZING RADIATION. I. THIAZOLIDINE DERIVATIVES
Effects of the proline analog L-thiazolidine-4-carboxylic acid on proline metabolism
Related Subjects
59 BASIC BIOLOGICAL SCIENCES
ANALGESICS
STRUCTURE-ACTIVITY RELATIONSHIPS
TOXICITY
OXIDOREDUCTASES
BIOCHEMICAL REACTION KINETICS
CARBON 14 COMPOUNDS
CYSTEINE
LIVER
MICE
PROLINE
TRACER TECHNIQUES
AMINES
AMINO ACIDS
ANIMALS
AZOLES
BODY
CARBOXYLIC ACIDS
CENTRAL NERVOUS SYSTEM DEPRESSANTS
DIGESTIVE SYSTEM
DRUGS
ENZYMES
GLANDS
HETEROCYCLIC ACIDS
HETEROCYCLIC COMPOUNDS
ISOTOPE APPLICATIONS
KINETICS
LABELLED COMPOUNDS
MAMMALS
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANIC SULFUR COMPOUNDS
ORGANS
PYRROLES
PYRROLIDINES
REACTION KINETICS
RODENTS
THIOLS
VERTEBRATES
560305* - Chemicals Metabolism & Toxicology- Vertebrates- (-1987)
550501 - Metabolism- Tracer Techniques