Platinum-based drugs and proteins: reactivity and relevance to DNA adduct formation.
Platinum-based drugs and proteins: reactivity and relevance to DNA adduct formation.
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DOI：
10.1016/j.jinorgbio.2013.01.007
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发表时间：
2013-05
影响因子：
3.9
通讯作者：
Sissi, Claudia
中科院分区：
文献类型：
--
作者：
Pinato, Odra;Musetti, Caterina;Farrell, Nicholas P.;Sissi, Claudia
临床使用的铂类药物的作用机制是通过在鸟嘌呤（N7）的7位氮上形成稳定的DNA加合物，并涉及一个或两个空间上封闭的残基。然而，蛋白质可以代表替代目标，因为特别是硫基团，存在于半胱氨酸或甲硫氨酸残基，可以有效地协调铂。在这里，我们表征了顺铂、反铂和两种反式铂胺衍生物（TPA）对三种不同蛋白质（牛α-乳清蛋白（α-LA）、鸡蛋溶菌酶（LYS）和人血清白蛋白（HSA））的反应性。我们的研究结果表明，通常测试的金属络合物与所选择的靶标反应，可能通过交联反应引起蛋白质寡聚化。有趣的是，这种过程的程度在很大程度上是由靶蛋白和金属络合物的化学特征调节的，TPA是最有效的铂化剂。从结构的角度来看，所得到的反应产物被证明是依赖于金属络合物的性质。然而，在所有情况下，也可以发生金属络合物到DNA的转移反应，从而保持核酸作为生物靶标的相关性。这些结果可用于更好地合理化顺铂和TPA报告的不同药理学特征，并有助于在系列中设计更具预测性的SAR。
The mechanism of action of clinically used Pt-based drugs is through the formation of stable DNA adducts occurring at the nitrogen in position 7 of guanine (N7) and involving one or two spatially closed residues. Nevertheless, proteins can represent alternative targets since in particular sulphur groups, present in cysteine or methionine residues, can efficiently coordinate platinum. Here we have characterized the reactivity profile of cisplatin, transplatin and of two trans-platinum amine derivatives (TPAs) towards three different proteins, bovine α-lactalbumin (α-LA), hen egg lysozyme (LYS) and human serum albumin (HSA). Our results demonstrate that generally the tested metal complexes react with the selected target causing protein oligomerization, likely through a cross-linking reaction. Interestingly, the extent of such a process is largely modulated by the target protein and by the chemical features of the metal complex, TPAs being the most efficient platinating agents. From a structural point of view the resulting reaction products turned out to be dependenting on the nature of the metal complexes. However, in all instances, a transfer reaction of the metal complex to DNA can also occur, maintaining the relevance of nucleic acids as a biological target. These results can be used to better rationalize the different pharmacological profiles reported for cisplatin and TPAs and can help in designing more predictive SARs within the series.
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影响因子：
3.4
作者：
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通讯作者：
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影响因子：
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