Salen-anthraquinone conjugates. Synthesis, DNA-binding and cleaving properties, effects on topoisomerases and cytotoxicity.
A series of amidoethylamino-anthraquinone derivatives bearing either one or two salen (bis(salicylidene)ethylenediamine) moieties complexed with CuII or NiII have been synthesized, and their DNA-binding and cleaving properties examined. The effects of the mono- and di-substituted anthracenedione-salen conjugates on DNA cleavage mediated by topoisomerases I and II have also been determined, as well as their cytotoxicity toward human KB cells. The anthraquinone-salen. NiII conjugates bind to GC-rich sequences in DNA, but do not cleave the macromolecule. By contrast, the anthraquinone-salen. CuII hybrids do not recognize particular nucleotide sequences but efficiently induce single-strand breaks in DNA after activation. The 5,8-dihydroxy-anthraquinone conjugates are more cytotoxic and more potent toward topoisomerase II than the non-hydroxylated analogues, but they are less cytotoxic than the salen-free anthraquinones. The attachment of a salen. CuII complex to the anthraquinone chromophore can confer DNA cleaving properties in vitro, but this is at the expense of cytotoxic activity. Anthraquinone-salen. CuII complexes may find useful employ as footprinting probes for investigating ligand-DNA interactions.
Routier
S
S
Laboratoire de Chimie Organique Physique, URA CNRS 351, Villeneuve d'Ascq, France.
Cotelle
N
N
Catteau
J P
JP
Bernier
J L
JL
Waring
M J
MJ
Riou
J F
JF
Bailly
C
C
D000880:Anthraquinones / Q000737:chemistry*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002614:Chelating Agents / Q000737:chemistry*; D003300:Copper / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004270:DNA, Circular / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy; D005029:Ethylenediamines / Q000737:chemistry*; D005609:Free Radicals; D006801:Humans; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D009532:Nickel / Q000378:metabolism; D010100:Oxygen
D000880:Anthraquinones; D002614:Chelating Agents; D004270:DNA, Circular; D005029:Ethylenediamines; D005609:Free Radicals; D003300:Copper; D009532:Nickel; D004247:DNA; C011452:disalicylaldehyde ethylenediamine; D004250:DNA Topoisomerases, Type II; D010100:Oxygen