Molecular pharmacology of hepsulfam, NSC 3296801: identification of alkylated nucleosides, alkylation site, and site of DNA cross-linking.
We have determined that hepsulfam, in common with its structural homologue busulfan, alkylates both free guanosine and GMP in DNA at the 7 nitrogen. Mass spectral analysis of the products of the reaction of hepsulfam with guanosine has identified the mono- and bis-alkylated guanosine adducts. UV spectrophotometry and mass spectrometry were used to confirm that alkylation occurred at the 7 nitrogen by following the formation of the formamidopyrimidyl form of the hepsulfam-guanosine adduct at high pH. We have also isolated and identified 1-guanyl,7-hydroxyheptane, 1-guanyl,7-sulfamylheptane, and 1,7-bis(guanyl)heptane from in vitro reaction mixtures of hepsulfam and calf thymus DNA. We have isolated bis-(7-formamidopyrimidyldeoxyguanosinyl)-heptane from an enzymatic digest of DNA treated with hepsulfam. Finally, we have found that hepsulfam forms interstrand cross-links at 5'-GXC-3' sites in model oligonucleotides.
Streeper
R T
RT
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Cotter
R J
RJ
Colvin
M E
ME
Hilton
J
J
Colvin
O M
OM
D000478:Alkylation; D001483:Base Sequence; D002851:Chromatography, High Pressure Liquid; D003198:Computer Simulation; D006151:Guanosine / Q000378:metabolism; D013058:Mass Spectrometry; D008956:Models, Chemical; D008969:Molecular Sequence Data; D009705:Nucleosides / Q000032:analysis; D013451:Sulfonic Acids / Q000737:chemistry* / Q000378:metabolism
D009705:Nucleosides; D013451:Sulfonic Acids; D006151:Guanosine; C052475:hepsulfam