Comparison of click-capable oxaliplatin and cisplatin derivatives to better understand Pt(ii)-induced nucleolar stress.

Autor:	Guerrero AS; Department of Chemistry and Biochemistry, University of Oregon Eugene OR USA derose@uoregon.edu., O'Dowd PD; Department of Chemistry, RCSI Dublin Ireland.; SSPC, the Science Foundation Ireland Research Centre for Pharmaceuticals Ireland., Pigg HC; Department of Chemistry and Biochemistry, University of Oregon Eugene OR USA derose@uoregon.edu., Alley KR; Department of Chemistry and Biochemistry, University of Oregon Eugene OR USA derose@uoregon.edu., Griffith DM; Department of Chemistry, RCSI Dublin Ireland.; SSPC, the Science Foundation Ireland Research Centre for Pharmaceuticals Ireland., DeRose VJ; Department of Chemistry and Biochemistry, University of Oregon Eugene OR USA derose@uoregon.edu.
Jazyk:	angličtina
Zdroj:	RSC chemical biology [RSC Chem Biol] 2023 Aug 16; Vol. 4 (10), pp. 785-793. Date of Electronic Publication: 2023 Aug 16 (Print Publication: 2023).
DOI:	10.1039/d3cb00055a
Abstrakt:	Pt(ii) chemotherapeutic complexes have been used as predominant anticancer drugs for nearly fifty years. Currently there are three FDA-approved chemotherapeutic Pt(ii) complexes: cisplatin, carboplatin, and oxaliplatin. Until recently, it was believed that all three complexes induced cellular apoptosis through the DNA damage response pathway. Studies within the last decade, however, suggest that oxaliplatin may instead induce cell death through a unique nucleolar stress pathway. Pt(ii)-induced nucleolar stress is not well understood and further investigation of this pathway may provide both basic knowledge about nucleolar stress as well as insight for more tunable Pt(ii) chemotherapeutics. Through a previous structure-function analysis, it was determined that nucleolar stress induction is highly sensitive to modifications at the 4-position of the 1,2-diaminocyclohexane (DACH) ring of oxaliplatin. Specifically, more flexible and less rigid substituents (methyl, ethyl, propyl) induce nucleolar stress, while more rigid and bulkier substituents (isopropyl, acetamide) do not. These findings suggest that a click-capable functional group can be installed at the 4-position of the DACH ring while still inducing nucleolar stress. Herein, we report novel click-capable azide-modified oxaliplatin mimics that cause nucleolar stress. Through NPM1 relocalization, fibrillarin redistribution, and γH2AX studies, key differences have been identified between previously studied click-capable cisplatin mimics and these novel click-capable oxaliplatin mimics. These complexes provide new tools to identify cellular targets and localization through post-treatment Cu-catalyzed azide-alkyne cycloaddition and may help to better understand Pt(ii)-induced nucleolar stress. To our knowledge, these are the first reported oxaliplatin mimics to include an azide handle, and cis -[(1 R ,2 R ,4 S ) 4-methylazido-1,2-cyclohexanediamine]dichlorido platinum(ii) is the first azide-functionalized oxaliplatin derivative to induce nucleolar stress. Competing Interests: There are no conflicts to declare. (This journal is © The Royal Society of Chemistry.)
Databáze:	MEDLINE
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