Department of Chemistry and Biochemistry, 1253 University of Oregon, Eugene, OR, 97403-1253, USA.
Institute of Molecular Biology, 1229 University of Oregon, Eugene, OR, 97403, USA.
J Biol Inorg Chem. 2019 Sep;24(6):899-908. doi: 10.1007/s00775-019-01707-9. Epub 2019 Sep 7.
Platinum anticancer therapeutics are widely used in a variety of chemotherapy regimens. Recent work has revealed that the cytotoxicity of oxaliplatin and phenanthriplatin is through induction of ribosome biogenesis stress pathways, differentiating them from cisplatin and other compounds that mainly work through DNA damage response mechanisms. To probe the structure-activity relationships in phenanthriplatin's ability to cause nucleolar stress, a series of monofunctional platinum(II) compounds differing in ring number, size and orientation was tested by nucleophosmin (NPM1) relocalization assays using A549 cells. Phenanthriplatin was found to be unique among these compounds in inducing NPM1 relocalization. To decipher underlying reasons, computational predictions of steric bulk, platinum(II) compound surface length and hydrophobicity were performed for all compounds. Of the monofunctional platinum(II) compounds tested, phenanthriplatin has the highest calculated hydrophobicity and volume but does not exhibit the largest distance from platinum(II) to the surface. Thus, spatial orientation and/or hydrophobicity caused by the presence of a third aromatic ring may be significant factors in the ability of phenanthriplatin to cause nucleolar stress.
铂类抗癌药物广泛应用于多种化疗方案中。最近的研究表明，奥沙利铂和菲咯嗪铂的细胞毒性是通过诱导核糖体生物发生应激途径，使它们与顺铂和其他主要通过 DNA 损伤反应机制起作用的化合物区分开来。为了探究菲咯嗪铂引起核仁应激的结构-活性关系，通过 A549 细胞的核仁磷蛋白（NPM1）重定位试验，对一系列在环数、大小和方向上不同的单功能铂（II）化合物进行了测试。结果发现，在这些化合物中，菲咯嗪铂在诱导 NPM1 重定位方面具有独特性。为了解释其潜在原因，对所有化合物的空间位阻、铂（II）化合物表面长度和疏水性进行了计算预测。在测试的单功能铂（II）化合物中，菲咯嗪铂具有最高的计算疏水性和体积，但与表面的距离并不最大。因此，第三个芳环的存在引起的空间取向和/或疏水性可能是菲咯嗪铂引起核仁应激能力的重要因素。
