Influence of Ring Modifications on Nucleolar Stress Caused by Oxaliplatin‐Like Compounds**
Influence of Ring Modifications on Nucleolar Stress Caused by Oxaliplatin‐Like Compounds**
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环修饰对奥沙利铂类似化合物引起的核仁应力的影响**
DOI：
10.1002/cbic.202200130
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发表时间：
2022
期刊：
影响因子：
3.2
通讯作者：
DeRose, Victoria J.
中科院分区：
文献类型：
--
作者：
McDevitt, Christine E.;Guerrero, Andres S.;Smith, Haley M.;DeRose, Victoria J.
奥沙利铂是一种广泛临床使用的铂类化合物，可通过核仁应激途径诱导细胞死亡，而不是其他Pt（II）化合物研究的典型DNA损伤反应。先前的研究发现，奥沙利铂1，2-二氨基环己烷（DACH）环而不是草酸酯离去基团对诱导核仁应激的能力很重要。在这里，我们研究了DACH环4位取代基对DACH-Pt（II）化合物引起核仁应力能力的影响。我们确定具有4-位甲基、乙基或丙基取代基的DACH-Pt（II）化合物诱导核仁应力，但具有4-异丙基取代基的DACH-Pt（II）化合物不诱导核仁应力。这种效应与取代基相对于配体的反式二胺是处于轴向位置还是赤道位置无关。这些结果表明，空间敏感的相互作用可能涉及铂化合物的能力，造成核仁应力。
Oxaliplatin, a platinum compound in broad clinical use, can induce cell death through a nucleolar stress pathway rather than the canonical DNA damage response studied for other Pt(II) compounds. Previous work has found that the oxaliplatin 1,2‐diaminocyclohexane (DACH) ring but not the oxalate leaving group is important to the ability to induce nucleolar stress. Here we study the influence of DACH ring substituents at the 4‐position on the ability of DACH−Pt(II) compounds to cause nucleolar stress. We determine that DACH−Pt(II) compounds with 4‐position methyl, ethyl, or propyl substituents induce nucleolar stress, but DACH−Pt(II) compounds with 4‐isopropyl substituents do not induce nucleolar stress. This effect is independent of whether the substituent is in the axial or equatorial position relative to thetransdiamines of the ligand. These results suggest that spatially sensitive interactions could be involved in the ability of platinum compounds to cause nucleolar stress.