The binding of [(en)Pt(mu-dpzm)2Pt(en)]4+ to G/C-rich regions of DNA.
The non-covalent binding of [(en)Pt(mu-dpzm)2Pt(en)]4+ to segments of DNA containing only G and C bases has been studied to gain an understanding of the pre-covalent binding association of cationic polynuclear platinum(II) anti-cancer drugs at G/C sites. 1H-NMR and CD spectroscopy were used to study the binding of the metal complex to the oligonucleotide d(GC)5 and the polynucleotide poly(dG-dC).poly(dG-dC), respectively. NOE contacts between the metal complex protons and the oligonucleotide sugar H1' protons observed in NOESY spectra indicated that the metal complex bound in the minor groove at the central C4 to G7 region of the oligonucleotide. This result indicates that even though cationic polynuclear platinum(II) complexes bind covalently in the major groove at G/C sites, the pre-covalent binding association is favoured in the minor groove. CD spectra indicated that the addition of the metal complex to poly(dG-dC)-poly(dG-dC) induced some conformational changes, but it was not possible to conclude that [(en)Pt(mu-dpzm)2Pt(en)]4+ induced a B- to Z-type DNA transition. In addition, in vitro transcription assays using the lac UV5 promoter showed that the non-covalent binding of [(en)Pt(mu-dpzm)2Pt(en)]4+ was sufficiently stable to inhibit transcription, and at particular sites.
Wheate
N J
NJ
School of Chemistry, University College, University of New South Wales, Australian Defence Force Academy, Canberra.
Cutts
S M
SM
Phillips
D R
DR
Aldrich-Wright
J R
JR
Collins
J G
JG
D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism; D001482:Base Composition; D001483:Base Sequence; D001665:Binding Sites; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation / Q000187:drug effects; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011089:Polydeoxyribonucleotides / Q000737:chemistry / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology
D000970:Antineoplastic Agents; D009838:Oligodeoxyribonucleotides; D009944:Organoplatinum Compounds; D011089:Polydeoxyribonucleotides; D011720:Pyrazoles; C415338:bis(4,4-dipyrazolylmethane-N,N')-bis(ethylenediamineplatinum(II)); C019530:poly(dC-dG); C052201:oligo(dG-dC); D004247:DNA