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 clickcapable
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 gH2AX 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.
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Influence of Ring Modifications on Nucleolar Stress Caused by Oxaliplatin‐Like Compounds**
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 the
- NSF-PAR ID:
- 10445424
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- ChemBioChem
- Volume:
- 23
- Issue:
- 14
- ISSN:
- 1439-4227
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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