title: Molecular pharmacology of hepsulfam, NSC 3296801: identification of alkylated nucleosides, alkylation site, and site of DNA cross-linking.
abstract: 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.
authors.affiliation: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors.forename: R T
authors.initials: RT
authors.lastname: Streeper
authors.forename: R J
authors.initials: RJ
authors.lastname: Cotter
authors.forename: M E
authors.initials: ME
authors.lastname: Colvin
authors.forename: J
authors.initials: J
authors.lastname: Hilton
authors.forename: O M
authors.initials: OM
authors.lastname: Colvin
mesh_terms: 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
chemical_list: D009705:Nucleosides; D013451:Sulfonic Acids; D006151:Guanosine; C052475:hepsulfam