Synthesis, DNA binding, topoisomerase II inhibition and cytotoxicity of two guanidine-containing anthracene-9,10-diones.
Two anthraquinone derivatives of the anticancer drugs mitoxantrone and ametantrone were examined for their ability to bind to DNA and to modulate the formation of topoisomerase-DNA cleavable complexes in vitro. The guanidinium groups introduced at the termini of the two aminoethylamino side chains of mitoxantrone can reinforce the interaction with DNA as judged from thermal denaturation studies with calf thymus DNA and polynucleotides. Footprinting experiments indicate that the binding to DNA of compound SR107 lacking the 5,8-hydroxyl substituents is essentially nonspecific whereas its congener SR 103 interacts preferentially with GC-rich sequences, particularly those containing 5'-(A/T)CG sites. Compound SR103, which bears two hydroxyl groups on the anthraquinone chromophore, promotes the cleavage of DNA by topoisomerase II and is cytotoxic toward human KB carcinoma cells in vitro. In contrast, the analogue SR107, which lacks OH groups, has no effect on topoisomerase II and is not cytotoxic.
Laboratoire de Chimie Organique Physique, URA 351 CNRS, USTL C3, Villeneuve d'Ascq, France.
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S
Routier
J L
JL
Bernier
J P
JP
Catteau
J F
JF
Riou
C
C
Bailly
D000880:Anthraquinones / Q000138:chemical synthesis* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001483:Base Sequence; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004247:DNA / Q000378:metabolism*; D018983:DNA Footprinting; D003850:Deoxyribonuclease I / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006146:Guanidines / Q000138:chemical synthesis* / Q000494:pharmacology; D006358:Hot Temperature; D006801:Humans; D007624:KB Cells; D008969:Molecular Sequence Data; D009691:Nucleic Acid Denaturation; D059005:Topoisomerase II Inhibitors
D000880:Anthraquinones; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006146:Guanidines; C113926:SR 103; C113925:SR 107; D059005:Topoisomerase II Inhibitors; D004247:DNA; D003850:Deoxyribonuclease I