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.

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单功能铂（II）化合物和核仁压力：菲铂是否独特？

铂类抗癌疗法广泛用于各种化疗方案中。最近的工作表明，奥沙利铂和菲铂的细胞毒性是通过诱导核糖体生物发生应激途径，将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。为了探究菲铂引起核仁压力的能力中的构效关系，使用A549细胞通过核磷蛋白（NPM1）重新定位分析测试了一系列环数，大小和方向不同的单官能铂（II）化合物。在这些化合物中，邻苯三铂在诱导NPM1重新定位中是独特的。为了解释根本原因，需要对空间体积进行计算预测，对所有化合物进行铂（II）化合物的表面长度和疏水性。在测试的单官能铂（II）化合物中，菲铂具有最高的计算疏水性和体积，但从铂（II）到表面的距离最大。因此，由第三芳环的存在引起的空间取向和/或疏水性可能是菲铂引起核仁压力的能力的重要因素。