Alkylation of nucleic acids by the antitumor agent COMC.
[reaction: see text]. Mass spectral data are presented indicating that the antitumor agent 2-crotonyloxymethyl-2-cyclohexenone (COMC) is capable of alkylating oligonucleotides via a mechanism involving an electrophilic exocyclic enone intermediate. Under physiological conditions, the exocyclic enone is likely the glutathionylated 2-exomethylenecyclohexenone. This supports a recent hypothesis that the antitumor activity of COMC arises from alkylation of nucleic acids and/or proteins critical to cell function and not from competitive inhibition of glyoxalase I by an adduct of COMC and glutathione.
Zhang
Qingrong
Q
Department of Chemistry and Biochemistry, University of Maryland, Baltimore County, Baltimore Maryland 21250, USA.
Ding
Zhebo
Z
Creighton
Donald J
DJ
Ganem
Bruce
B
Fabris
Daniele
D
D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis / Q000494:pharmacology*; D003512:Cyclohexanones / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007791:Lactoylglutathione Lyase / Q000037:antagonists & inhibitors; D013058:Mass Spectrometry; D008970:Molecular Weight; D009363:Neoplasm Proteins / Q000737:chemistry; D009696:Nucleic Acids / Q000737:chemistry* / Q000187:drug effects; D009841:Oligonucleotides / Q000737:chemistry; D021241:Spectrometry, Mass, Electrospray Ionization
D000903:Antibiotics, Antineoplastic; D003512:Cyclohexanones; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D009696:Nucleic Acids; D009841:Oligonucleotides; C073431:2-crotonyloxymethyl-2-cyclohexenone; D007791:Lactoylglutathione Lyase