Issue 10, 2023

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

Abstract

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-[(1R,2R,4S) 4-methylazido-1,2-cyclohexanediamine]dichlorido platinum(II) is the first azide-functionalized oxaliplatin derivative to induce nucleolar stress.

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

Supplementary files

Article information

Article type
Paper
Submitted
18 Apr. 2023
Accepted
16 Aug. 2023
First published
16 Aug. 2023
This article is Open Access
Creative Commons BY-NC license

RSC Chem. Biol., 2023,4, 785-793

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

A. S. Guerrero, P. D. O’Dowd, H. C. Pigg, K. R. Alley, D. M. Griffith and V. J. DeRose, RSC Chem. Biol., 2023, 4, 785 DOI: 10.1039/D3CB00055A

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