Monofunctional platinum amine complexes destabilize DNA significantly

Both cis-[Pt(NH(3))(2)(4-Me-Py)Cl](+) and trans-[Pt(NH(3))(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(NH(3))(2)(4-Me-Py)Cl](+) and trans-[Pt(NH(3))(2)(4-Me-Py)Cl](+), the interactions of these two platinum compounds with the DNA heptamer CCTG*TCC:GGA-CAGG duplex (G* is the platinated guanine) have been examined. The reaction rate of cis-[Pt(NH(3))(2)(4Me-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 (T(m)) 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(NH(3))(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.