title: Inhibitory activity and mechanism of inhibition of the N-[[(4-benzoylamino)phenyl]sulfonyl]amino acid aldose reductase inhibitors.
abstract: A series of substituted N-[[(4-benzoylamino)phenyl]sulfonyl]amino acids (BAPS-amino acids) were synthesized by established methods, and the stereochemistry of the products was confirmed by HPLC analysis after chiral derivatization. When tested against aldose reductase (alditol:NADP+ oxidoreductase; EC 1.1.1.21; ALR2) isolated from rat lens, all of the BAPS-amino acids were determined to be significantly more inhibitory than the corresponding N-(phenylsulfonyl)amino acids. Structure-inhibition and enzyme kinetic analyses suggest that the BAPS-amino acids inhibit ALR2 by a mechanism similar to the N-(phenylsulfonyl)amino acids. However, multiple inhibition analyses indicate that the increased inhibitory activity of the BAPS-amino acids is a result of interaction with multiple sites present on ALR2. Enzyme specificity studies with several of the BAPS-amino acids demonstrated that these compounds do not produce significant inhibition of other nucleotide-requiring enzymes including aldehyde reductase (alcohol: NADP+ oxidoreductase; EC 1.1.1.2; ALR1).
authors.affiliation: Department of Pharmacal Sciences, School of Pharmacy, Auburn University, AL 36849-5503.
authors.forename: J
authors.initials: J
authors.lastname: DeRuiter
authors.forename: C A
authors.initials: CA
authors.lastname: Mayfield
mesh_terms: D000429:Alcohol Oxidoreductases / Q000378:metabolism; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D000596:Amino Acids / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D002851:Chromatography, High Pressure Liquid; D005998:Glycine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D007700:Kinetics; D007908:Lens, Crystalline / Q000201:enzymology; D051381:Rats; D013237:Stereoisomerism; D013450:Sulfones / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D000596:Amino Acids; D013450:Sulfones; C062604:N-(((4-benzoylamino)phenyl)sulfonyl)glycine; D000429:Alcohol Oxidoreductases; D000449:Aldehyde Reductase; D005998:Glycine