The berenil ligand directs the DNA binding of the cytotoxic drug Pt-berenil.
To determine the affinity towards DNA sequences of novel antitumor drugs in comparison with their parental compounds may lead to the design of new analogous drugs with improved antitumor activity. Thus, the affinities of Pt-berenil towards different DNA sites relative to cis-DDP and berenil drugs were analysed using DNase I footprinting and restriction endonuclease analysis. The data show that the Pt-berenil drug inhibits the cutting activity of Hind III enzyme to the same extent as the berenil ligand. In contrast, inhibition by Pt-berenil of the cutting activity of Bam HI enzyme is significantly lower than that of cis-DDP. These results indicate that although the cis-Pt(II) centres of Pt-berenil maintain certain affinity toward G + C regions, which are the main binding sequences of cis-DDP, however, the berenil ligand seems to direct the Pt-berenil molecule towards A + T regions, which are the binding sequences preferred by berenil. In fact, 1H- and 195Pt-NMR spectra of Pt-berenil:nucleoside complexes show that Pt-berenil not only covalently binds to N7 of guanosine but also to N1/N7 of adenosine.
González
V M
VM
Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Facultad de Ciencias, Universidad Autónoma de Madrid, Spain.
Pérez
J M
JM
Alonso
C
C
D000241:Adenosine / Q000378:metabolism; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology; D001665:Binding Sites; D002945:Cisplatin / Q000494:pharmacology; D004247:DNA / Q000378:metabolism*; D018983:DNA Footprinting; D015245:Deoxyribonuclease BamHI / Q000037:antagonists & inhibitors / Q000378:metabolism; D015247:Deoxyribonuclease HindIII / Q000037:antagonists & inhibitors / Q000378:metabolism; D003850:Deoxyribonuclease I / Q000378:metabolism; D004133:Diminazene / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006151:Guanosine / Q000378:metabolism; D007364:Intercalating Agents / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D009944:Organoplatinum Compounds / Q000378:metabolism* / Q000494:pharmacology
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007364:Intercalating Agents; D009944:Organoplatinum Compounds; C110112:platinum-berenil; D006151:Guanosine; D004247:DNA; D015245:Deoxyribonuclease BamHI; D015247:Deoxyribonuclease HindIII; D003850:Deoxyribonuclease I; C003915:diminazene aceturate; D000241:Adenosine; D002945:Cisplatin; D004133:Diminazene