DNA interstrand cross-linking, DNA sequence specificity, and induced conformational changes produced by a dimeric analog of (+)-CC-1065

Z. M. Ding, L. H. Hurley

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

U-77779 is a symmetrical dimer of the spirocyclopropyl allkylating subunit of (+)-CC-1065 in which the linker consists of two indole subunits separated by a ureido group. This compound was synthesized by scientists of the Upjohn Company and was found to be more active in both anti-tumor efficacy and cytotoxicity than its mono-alkylating analogs. Using three different 21-base pair DNA duplexes containing U-77779 reactive sequences, we have shown that U-77779 produces a stable interstrand cross-linked species that loses its internal self complementarity. A comparison of U-77779 with the mono-alkylating analogs of (+)-CC-1065 shows that it appears to have an increased sequence selectivity such that, while monoalkylating compounds like (+)-CC-1065 react at more than one site, U-77779 reacts only at sites where there are two suitably positioned alkylation sites. Chemical footprinting with 1,10-phenanthroline-copper complex revealed a six base pair cross-linked region between the two covalently modified adenines with modulated cleavage outside this region. In the case of hydroxyl radical footprinting, considerable variability of the extent of cleavage within the cross-linked sequence was found. These results are discussed in terms of likely induced conformational changes in DNA. In contrast to (+)-CC-1065, non-denaturing gel electrophoresis did not reveal any net bending of DNA due to U-77779, which we believe is due to the 180 out-of-phase bending produced on opposite strands of DNA by the cross-linker.

Original languageEnglish (US)
Pages (from-to)427-452
Number of pages26
JournalAnti-Cancer Drug Design
Volume6
Issue number5
StatePublished - Dec 1 1991
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Oncology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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