Characterization of the sequential non-covalent and covalent interactions of the antitumour antibiotic hedamycin with double stranded DNA by NMR spectroscopy.
Hedamycin, a member of the pluramycin class of antitumour antibiotics, consists of a planar anthrapyrantrione chromophore to which is attached two aminosugar rings at one end and a bisepoxide-containing sidechain at the other end. Binding to double-stranded DNA is known to involve both reversible and non-reversible modes of interaction. As a part of studies directed towards elucidating the structural basis for the observed 5'-pyGT-3' sequence selectivity of hedamycin, we conducted one-dimensional NMR titration experiments at low temperature using the hexadeoxyribonucleotide duplexes d(CACGTG)(2) and d(CGTACG)(2). Spectral changes which occurred during these titrations are consistent with hedamycin initially forming a reversible complex in slow exchange on the NMR timescale and binding through intercalation of the chromophore. Monitoring of this reversible complex over a period of hours revealed a second type of spectral change which corresponds with formation of a non-reversible complex.
Pavlopoulos
S
S
Department of Medicinal Chemistry, Victorian College of Pharmacy, Monash University, Melbourne, Victoria, Australia.
Bicknell
W
W
Wickham
G
G
Craik
D J
DJ
D000477:Alkylating Agents / Q000737:chemistry* / Q000378:metabolism; D000617:Aminoglycosides; D000880:Anthraquinones / Q000737:chemistry* / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000737:chemistry* / Q000378:metabolism; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003080:Cold Temperature; D004247:DNA / Q000378:metabolism*; D007364:Intercalating Agents / Q000737:chemistry* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009838:Oligodeoxyribonucleotides / Q000378:metabolism; D013329:Structure-Activity Relationship; D013997:Time Factors; D017186:Titrimetry
D000477:Alkylating Agents; D000617:Aminoglycosides; D000880:Anthraquinones; D000900:Anti-Bacterial Agents; D000903:Antibiotics, Antineoplastic; D007364:Intercalating Agents; D009838:Oligodeoxyribonucleotides; C001328:hedamycin; C063717:altromycin B; D004247:DNA