Structure-activity relationships for reactivity of carbonyl-containing compounds with glutathione.
For toxicological-based structure-activity relationships to advance, will require a better understanding of molecular reactivity. A rapid and inexpensive spectrophotometric assay for determining the reactive to glutathione (GSH) was developed and used to determine GSH reactivity (reactGSH) data for 21 aliphatic derivatives of esters, ketones and aldehydes. From these data, a series of structure-activity relationships were evaluated. The structure feature associated with reactGSH was an acetylenic or olefinic moiety conjugated to a carbonyl group (i.e. polarized alpha,beta-unsaturation). This structure conveys the capacity to undergo a covalent interaction with the thiol group of cysteine (i.e. Michael- addition). Quantitatively reactGSH of the alpha,beta-unsaturated carbonyl compounds is reliant upon the specific molecular structure with several tendencies observed. Specifically, it was noted that for alpha,beta-unsaturated carbonyl compounds: (1) the acetylenic-substituted derivatives were more reactive than the corresponding olefinic-substituted ones; (2) terminal vinyl-substituted derivatives was more reactive than the internal vinylene-substituted ones; (3) methyl substitution on the vinyl carbon atoms diminishes reactivity and methyl-substitution on the carbon atom farthest from the carbonyl group causes a larger reduction; (4) derivatives with carbon-carbon double bond on the end of the molecule (i.e. vinyl ketone) were more reactive than one with the carbon-oxygen bond at the end of the molecule (i.e. aldehyde) and (5) the ester with an additional unsaturated vinyl groups were more reactive than the derivative having an unsaturated ethyl group.
Schultz
T W
TW
The University of Tennessee, College of Veterinary Medicine, Department of Comparative Medicine, Room A205, 2407 River Drive, Knoxville, TN 37996-4543, USA. tschultz@utk.edu
Yarbrough
J W
JW
Johnson
E L
EL
D000171:Acrolein / Q000737:chemistry; D000475:Alkenes / Q000737:chemistry; D002244:Carbon / Q000737:chemistry*; D003437:Crotonates / Q000737:chemistry; D005978:Glutathione / Q000737:chemistry*; D008689:Methacrylates / Q000737:chemistry; D008745:Methylation; D013329:Structure-Activity Relationship
D000475:Alkenes; D003437:Crotonates; D008689:Methacrylates; D002244:Carbon; D000171:Acrolein; C117224:1-hexene; D005978:Glutathione