Mechanistic studies of a novel class of trisubstituted platinum(II) antitumor agents.
Mechanistic studies of a novel class of trisubstituted platinum(II) antitumor agents.
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发表时间：
1991-04
期刊：
影响因子：
11.2
通讯作者：
L. Hollis;W. Sundquist;J. Burstyn;W. Heiger-Bernays;S. Bellon;K. J. Ahmed;A. R. Amundsen;E. Stern;S. Lippard
中科院分区：
文献类型：
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作者：
L. Hollis;W. Sundquist;J. Burstyn;W. Heiger-Bernays;S. Bellon;K. J. Ahmed;A. R. Amundsen;E. Stern;S. Lippard
化学和生物学研究提出了一个新的系列铂（II）抗肿瘤剂，违反了经典的结构-活性关系建立铂配合物。这些新的药物，已被证明对小鼠和人类肿瘤系统的活性，是顺式-[Pt（NH 3）2（Am）Cl]+阳离子，其中Am是吡啶，嘧啶，嘌呤或苯胺的衍生物。该系列的成员在体外阻断猿猴病毒40的DNA复制，并在复制作图实验中抑制DNA聚合酶对单个鸟嘌呤残基的作用。在竞争性酶联免疫吸附试验研究中使用了选择性结合小牛胸腺DNA上顺铂病变的单克隆抗体，以证明铂-三胺复合物不会在DNA上产生顺铂和通式为cis-[Pt（胺）2X2]的类似物所特有的链内交联类型。这些结果表明，顺式-[Pt（NH3）2（Am）Cl]+阳离子在DNA上形成单功能加合物，而不是消除NH3或Am以提供双功能损伤。这一结论进一步支持的核磁共振光谱和酶消化分析的这些三胺配合物与d（GpG）和dG，这也揭示了单功能结合的反应的产物。然而，当顺式-[Pt（NH3）2（4-Br-吡啶）Cl]+在磷酸盐缓冲盐水中在37 ℃下放置14天时，释放出NH 4+，同时形成反式-[Pt（NH3）（4-Br-吡啶）Cl 2]。该化合物通过单晶X-射线衍射研究表征，其详细情况报道。然而，反式-[Pt（NH3）（4-Br-吡啶）Cl 2]不显示抗癌活性的事实表明，其由顺式-[Pt（NH3）2（4-Br-吡啶）Cl]+形成不是这种铂-三胺络合物作用机制的重要组成部分。两者合计，这些研究结果表明，顺式-[Pt（NH 3）2（Am）Cl]+配合物的细胞毒性最有可能产生的单官能加合物的形成。与这类新的抗肿瘤药物相关的DNA结合特性表明，它们可能显示出与顺铂和相关类似物不同的活性特征。
Chemical and biological studies are presented for a new series of platinum(II) antitumor agents that violate the classical structure-activity relationships established for platinum complexes. These new agents, which have demonstrated activity against murine and human tumor systems, are cis-[Pt(NH3)2(Am)Cl]+ cations, in which Am is a derivative of pyridine, pyrimidine, purine, or aniline. Members from this series block simian virus 40 DNA replication in vitro and inhibit the action of DNA polymerases at individual guanine residues in replication mapping experiments. Monoclonal antibodies that bind selectively to cisplatin lesions on calf thymus DNA were used in a competitive enzyme-linked immunosorbent assay study to show that the platinum-triamine complexes do not produce the type of intrastrand cross-links on DNA that are characteristics of cisplatin and analogues with the general formula cis-[Pt(amine)2X2]. These results indicate that cis-[Pt(NH3)2(Am)Cl]+ cations form monofunctional adducts on DNA rather than eliminate NH3 or Am to afford bifunctional lesions. This conclusion is further supported by nuclear magnetic resonance spectroscopic and enzymatic digestion analyses of the products of the reactions of these triamine complexes with d(GpG) and dG, which also reveal monofunctional binding. When cis-[Pt(NH3)2(4-Br-pyridine)Cl]+ was allowed to stand in phosphate-buffered saline at 37 degrees C for 14 days, however, NH4+ was released and trans-[Pt(NH3)(4-Br-pyridine)Cl2] formed concomitantly. This compound was characterized by a single crystal X-ray diffraction study, the details of which are reported. The fact that trans-[Pt(NH3)(4-Br-pyridine)Cl2] displays no anticancer activity, however, indicates that its formation from cis-[Pt(NH3)2(4-Br-pyridine)Cl]+ is not a significant component of the mechanism of action of this platinum-triamine complex. Taken together, these findings indicate that the cytotoxicity of cis-[Pt(NH3)2(Am)Cl]+ complexes most likely arises from the formation of monofunctional adducts. The DNA binding properties associated with this new class of antitumor agents suggest that they may display an activity profile different from that of cisplatin and related analogues.