Platinum(II) chemotherapeutic complexes have been utilized extensively in the clinic as anticancer drugs for several decades. The Pt(II) compounds carboplatin, oxaliplatin and phenanthriplatin were developed in an effort to mitigate side effects induced by cisplatin. All of these complexes have long been thought to induce cellular apoptosis through the DNA damage response pathway. However, more recent studies indicate that oxaliplatin and phenanthriplatin may induce cell death through an alternative pathway known as nucleolar stress. Treatment with these specific Pt(II) complexes inhibit regular nucleolar processes such as ribosome biogenesis, causing a stress response similar to that induced by known small organic molecules such as Actinomycin D. Further investigations are needed to obtain a better understanding of how platinum compounds might influence the nucleolus. Our first approach was to probe nucleolar stress induction sensitivity through a structure-function analysis by modifying the 4- position of the 1,2-diaminocyclohexane (DACH) ring of oxaliplatin. It was identified that nucleolar stress is highly sensitive to substituent modifications on the DACH ring. Informed by these findings, the development of a novel click-capable oxaliplatin mimic, cis-[(1R,2R,4S) 4-methylazido-1,2-cyclohexanediamine]dichlorido platinum(II), was achieved along with a suite of novel click-capable phenanthriplatin mimics, cis-[Pt(NH₃)₂(azidophenanthridine)Cl]NO₃, which were characterized through an array of nucleolar stress assays. These complexes provide a new approach to identify cellular targets through post-treatment Cu-catalyzed azide–alkyne cycloaddition and may help to better understand Pt(II)-induced nucleolar stress.

Paul O'Dowd

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