Triplex-Directed Interstrand DNA Cross-Linking by Diaziridinylquinone−Oligonucleotide Conjugates

• Published in: Journal of the American Chemical Society Vol. 120; no. 38; pp. 9729 - 9734
• Main Authors: Reed, Michael W, Wald, Ansel, Meyer, Rich B
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 30.09.1998; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Multidisciplinary; Diaziridinylquinone; oligonucleotides; Physical Sciences; Science & Technology; DOUBLE-HELICAL DNA; AZIRIDINYLBENZOQUINONES; DT-DIAPHORASE; FORMING OLIGONUCLEOTIDE; HUMAN-CELLS; ALKYLATION; DOUBLE-STRANDED DNA; COVALENT STRUCTURE; PSORALEN; SEQUENCE SELECTIVITY
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja973819u

Triplex-forming oligonucleotides (TFOs) bind in the major groove to specific double-helical DNA sequences and have been shown to inhibit the function of targeted genes. Diaziridinylquinones are bifunctional alkylating agents that can form interstrand cross-links in DNA at 5‘-GNC sites. To demonstrate the feasibility of targeted interstrand cross-linking, a diaziridinylquinone−TFO conjugate was prepared from a diaziridinylquinone intermediate bearing an activated ester linker. The first demonstration of triplex-directed interstrand DNA cross-linking by a single targeted bifunctional alkylating agent is described. Up to 38% interstrand cross-linking was observed at pH 6.2.