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Molecular Pharmacology of Hepsulfam, NSC 3296801: Identification of Alkylated Nucleosides, Alkylation Site, and Site of DNA Cross-Linking¹

Department of Pharmacology and Molecular Sciences [R. T. P., R. J. C., O. M. C.] and Oncology Center [J. H., O. M. C.], The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, and the Center for Computational Engineering, Sandia National Laboratories, Livermore, California 94551 [M. E. C.]

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.

¹ These studies were supported by by USPHS Training Grant CA09243 14 (R. T. S.), NIH-National Cancer Institute Grants 2RO1CA16783-1 and 5P01CA15396-19 (O. M. C.), and by National Science Foundation Grant DIR 90-16567 (R. J. C.). Mass spectra were obtained in the Middle Atlantic Mass Spectrometry Laboratory, a National Science Foundation Shared Instrument Facility.

² To whom requests for reprints should be addressed, at The Johns Hopkins Oncology Center, 600 North Wolfe Street, Oncology 1-121, Baltimore, MD 21287-8934.

Received 11/15/94. Accepted 2/ 3/95.