Effect of Thioethers on DNA Platination by trans-Platinum Complexes
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- 作者：Chan Li ; Rongrong Huang ; Yi Ding ; Einar Sletten ; Fabio Arnesano ; Maurizio Losacco ; Giovanni Natile ; Yangzhong Liu
- 刊名：Inorganic Chemistry
- 出版年：2011
- 出版时间：September 5, 2011
- 年：2011
- 卷：50
- 期：17
- 页码：8168-8176
- 全文大小：978K
- 年卷期：v.50,no.17(September 5, 2011)
- ISSN：1520-510X
文摘
Increasing evidence indicates that sulfur-containing molecules can play important roles in the activity of platinum anticancer drugs. Although nuclear DNA is retained to be the ultimate target, these platinum compounds can readily react with a variety of other substrates containing a soft donor atom, such as proteins, peptides, and low molecular weight biomolecules, before reaching DNA. In a recent study it was demonstrated that the DNA platination rate of a trans-geometry antitumor drug was dramatically enhanced by methionine binding, thus suggesting that the thioether could serve as a catalyst for DNA platination. In this work we performed detailed studies on the reactions of a widely investigated and very promising trans-platinum complex having two iminoethers and two chlorido ligands, trans-EE, with methionine (Met) and guanosine 5鈥?monophosphate (GMP). The results show that in the reaction of trans-EE with methionine the bisadduct is the dominant species in the early stage of the reaction. The reaction is also influenced by chloride concentration: at low NaCl the bis-methionine adduct is formed in preference, whereas the monoadduct is favored at high NaCl concentration. Not only the monomethionine complex, trans-PtCl(E-iminoether)2(AcMet), but also the bis-methionine adduct, trans-Pt(E-iminoether)2(AcMet)2, which has already lost both leaving chlorides, can react with GMP to form the ternary platinum complex trans-Pt(E-iminoether)2(AcMet)(GMP). The latter reaction discloses the possibility of direct coordination to DNA of a platinum鈥損rotein adduct, in which the two carrier ligands remain intact; this is not the case of cis-oriented platinum complexes, like cisplatin, for which formation of a ternary complex is usually accompanied by loss of at least one carrier ligand. Interestingly, isomerization from S to N coordination of one methionine takes place in the bis-methionine complex at neutral pH, while the monoadduct appears to be stable. The shift from S to N coordination of one methionine in the trans-bis-methionine adduct can easily account for the obtainment of the cis isomer in the bis-chelated Pt(Met-S,N)2 end product.