Bauer C, Peleg-Shulman T, Gibson D, Wang A H
Department of Chemistry, University of Illinois at Urbana-Champaign, USA.
Eur J Biochem. 1998 Sep 1;256(2):253-60. doi: 10.1046/j.1432-1327.1998.2560253.x.
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 CCTGTCC: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.
顺式-[Pt(NH₃)₂(4-Me-Py)Cl]⁺和反式-[Pt(NH₃)₂(4-Me-Py)Cl]⁺均在鸟嘌呤残基的N7位点与DNA共价结合，形成单齿加合物。然而，与顺铂和反铂一样，只有顺式异构体具有抗癌活性，而反式异构体则没有。为了理解与顺式-[Pt(NH₃)₂(4-Me-Py)Cl]⁺和反式-[Pt(NH₃)₂(4-Me-Py)Cl]⁺相关的不同活性的分子基础，已研究了这两种铂化合物与DNA七聚体CCTGTCC:GGACAGG双链体（G为铂化鸟嘌呤）的相互作用。顺式-[Pt(NH₃)₂(4-Me-Py)Cl]⁺与单链CCTGTCC的反应速率明显快于反式异构体。已通过二维核磁共振光谱研究了铂-DNA加合物的溶液结构。顺铂加合物和反铂加合物均会使DNA双链体显著不稳定。通过核磁共振估计，铂化七聚体双链体的解链温度（Tm）比未铂化的双链体低10摄氏度。在2摄氏度时，位于寡核苷酸5'侧、超出铂损伤位点的碱基对会被破坏。随着时间的推移，铂-DNA复合物分解，顺式-[Pt(NH₃)₂(4-Me-Py)]铂复合物逐渐从DNA上脱离。未观察到链间交联。讨论了结构研究的生物学意义。
