Interaction of the nonintercalative antitumour drugs SN-6999 and SN-18071 with DNA: influence of ligand structure on the binding specificity.
Binding to DNA's of the non-intercalative ligands SN-6999 and SN-18071 has been studied by means of circular dichroism, UV absorption, thermal melting and for SN-6999 by viscosity measurements. Both antitumour drugs show a preference for dA.dT rich DNA's, but the base pair selectivity of SN-18071 is lower as indicated by some affinity to dG.dC containing duplex DNA. The dA.dT base pair specificity of SN-6999 is comparable to that of netropsin. It forms very stable complexes with dA.dT containing duplex DNA and competes with netropsin binding on DNA. The ligands SN-18071 and pentamidine are totally released from their complexes with poly(dA-dT).poly(dA-dT) by competitive netropsin binding. The results demonstrate that hydrogen bonding capacity of the ligand in addition to other factors strongly contribute to the base sequence specificity in the recognition process of the ligand with DNA. A binding model of SN-6999 with five dA.dT pairs in the minor groove of B-DNA is suggested.
Luck
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Akademie der Wissenschaften der DDR, Zentralinstitut für Mikrobiologie und Experimentelle Therapie, Jena, G.D.R.
Reinert
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Baguley
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Zimmer
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D000970:Antineoplastic Agents / Q000378:metabolism*; D001482:Base Composition; D001667:Binding, Competitive; D002942:Circular Dichroism; D004247:DNA / Q000378:metabolism*; D008958:Models, Molecular; D009429:Netropsin / Q000378:metabolism; D009691:Nucleic Acid Denaturation; D010419:Pentamidine / Q000378:metabolism; D011726:Pyridinium Compounds / Q000378:metabolism*; D011806:Quinolinium Compounds / Q000378:metabolism*; D013056:Spectrophotometry, Ultraviolet; D014783:Viscosity
D000970:Antineoplastic Agents; D011726:Pyridinium Compounds; D011806:Quinolinium Compounds; C041350:NSC 101327; D009429:Netropsin; D010419:Pentamidine; C040228:SN 18071; C062476:SN 6999; D004247:DNA