Monofunctional platinum amine complexes destabilize DNA significantly.
Both cis-[Pt(NH3)2(4-Me-Py)Cl]+ and trans-[Pt(NH3)2(4-Me-Py)Cl]+ bind DNA covalently at the N7 site of guanine residues forming mono-dentate adducts. However, like cisplatin and transplatin, only the cis isomer has anti-cancer activity, whereas the trans-isomer does not. In order to understand the molecular basis of the different activities associated with cis-[Pt(NH3)2(4-Me-Py)Cl]+ and trans-[Pt(NH3)2(4-Me-Py)Cl]+, the interactions of these two platinum compounds with the DNA heptamer CCTG*TCC:GGACAGG duplex (G* is the platinated guanine) have been examined. The reaction rate of cis-[Pt(NH3)2(4-Me-Py)Cl]+ with the single-stranded CCTGTCC is significantly faster than that of the trans isomer. The solution structure of the platinum-DNA adducts has been studied by two-dimensional NMR spectroscopy. Both the cis-platinum adducts and the trans-platinum adducts destabilize the DNA duplex significantly. The melting temperature (Tm) of the platinated heptamer duplex is estimated to be 10 degrees C lower than for the unplatinated duplex by NMR. At 2 degrees C, the base pairs located on the 5' side of the oligonucleotide, beyond the platinum lesion site, are disrupted. Over time, the platinum-DNA complex decomposes and the cis-[Pt(NH3)2(4-Me-Py)] platinum complex is gradually detached from DNA. No interstrand crosslinking is observed. The biological implications of the structural studies are discussed.
Bauer
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Department of Chemistry, University of Illinois at Urbana-Champaign, USA.
Peleg-Shulman
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T
Gibson
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Wang
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AH
D000588:Amines / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D002945:Cisplatin / Q000031:analogs & derivatives*; D004247:DNA / Q000737:chemistry; D007536:Isomerism; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D009944:Organoplatinum Compounds / Q000737:chemistry*; D017671:Platinum Compounds / Q000737:chemistry*
D000588:Amines; D000970:Antineoplastic Agents; D009838:Oligodeoxyribonucleotides; D009944:Organoplatinum Compounds; D017671:Platinum Compounds; C114912:platinum diamino-4-methylpyridine chloride; D004247:DNA; D002945:Cisplatin