Synthesis and metabolism of inhibitors of ribonucleotide reductase

Thesis/Dissertation · Tue Jan 01 04:00:00 EST 1985

OSTI ID:6898768

Smith, F T

In an effort to prepare more effective inhibitors of ribo-nucleotide reductase a series of 2-substituted-4,6-dihydroxypyrimidines was prepared via the appropriately substituted benzamidine. None of the compounds exhibited in vivo activity against L1210 leukemia. No further testing was performed. In order to investigate the metabolism of 3,4-dihydroxybenzohydroxamic acid, a known inhibitor of ribonucleotide reductase, radiolabeled 3,4-dihydroxybenzohydroxamic acid was synthesized by a modification of the procedure of Pichat and Tostain. /sup 14/C-3,4-Dihydroxybenzoic acid was converted to the methyl ester and subsequently reacted with hydroxylamine to give the hydroxamic acid. /sup 14/C-3,4-Dihydroxybenzohydroxamic acid was given i.p. to Sprague-Dawley rats. Excretion occurred mainly (72%) via the urine. HPLC coupled with GC/MS analyses showed that the compound was excreted mainly unchanged. The compound was metabolized to 3,4-dihydroxybenzamide, 4-methoxy-3-hydroxybenzohydroxamic acid, and 4-hydroxy-3-methoxybenzohydroxamic acid. HPLC analysis also showed the lack of formation of any glucuronide or sulfate conjugates through either the hydroxamic acid or catechol functionalities.

• Research Organization: Virginia Commonwealth Univ., Richmond (USA)
• OSTI ID: 6898768
• Country of Publication: United States
• Language: English

Related Subjects

550201* -- Biochemistry-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
AMINES
ANIMALS
BIOLOGICAL MATERIALS
BIOLOGICAL WASTES
BIOSYNTHESIS
BODY FLUIDS
CARBON 14 COMPOUNDS
CHROMATOGRAPHY
CLEARANCE
ENZYME INHIBITORS
ENZYMES
EXCRETION
HYDROXAMIC ACIDS
HYDROXY COMPOUNDS
LABELLED COMPOUNDS
LIQUID COLUMN CHROMATOGRAPHY
MAMMALS
MATERIALS
METABOLISM
METABOLITES
ORGANIC COMPOUNDS
OXIDOREDUCTASES
RATS
RODENTS
SEPARATION PROCESSES
SYNTHESIS
URINE
VERTEBRATES
WASTES