Hollis L S, Sundquist W I, Burstyn J N, Heiger-Bernays W J, Bellon S F, Ahmed K J, Amundsen A R, Stern E W, Lippard S J
Department of Chemistry, Massachusetts Institute of Technology, Cambridge 02139.
Cancer Res. 1991 Apr 1;51(7):1866-75.
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.
本文介绍了一系列新的铂（II）抗肿瘤药物的化学和生物学研究，这些药物违反了为铂配合物建立的经典构效关系。这些新药物已证明对小鼠和人类肿瘤系统具有活性，它们是顺式-[Pt(NH₃)₂(Am)Cl]⁺阳离子，其中Am是吡啶、嘧啶、嘌呤或苯胺的衍生物。该系列中的成员在体外阻断猿猴病毒40 DNA复制，并在复制图谱实验中抑制DNA聚合酶在单个鸟嘌呤残基处的作用。在竞争性酶联免疫吸附测定研究中，使用了选择性结合小牛胸腺DNA上顺铂损伤的单克隆抗体，结果表明铂三胺配合物不会在DNA上产生顺铂和通式为顺式-[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以产生双功能损伤。这些三胺配合物与d(GpG)和dG反应产物的核磁共振光谱和酶消化分析进一步支持了这一结论，这些分析也揭示了单功能结合。然而，当顺式-[Pt(NH₃)₂(4-溴吡啶)Cl]⁺在37℃的磷酸盐缓冲盐水中放置14天时，会释放出NH₄⁺并同时形成反式-[Pt(NH₃)(4-溴吡啶)Cl₂]。通过单晶X射线衍射研究对该化合物进行了表征，并报告了详细情况。然而，反式-[Pt(NH₃)(4-溴吡啶)Cl₂]没有抗癌活性，这一事实表明它由顺式-[Pt(NH₃)₂(4-溴吡啶)Cl]⁺形成并非该铂三胺配合物作用机制的重要组成部分。综上所述，这些发现表明顺式-[Pt(NH₃)₂(Am)Cl]⁺配合物的细胞毒性很可能源于单功能加合物的形成。与这类新的抗肿瘤药物相关的DNA结合特性表明，它们可能表现出与顺铂及相关类似物不同的活性谱。
