skip to main content
US FlagAn official website of the United States government
dot gov icon
Official websites use .gov
A .gov website belongs to an official government organization in the United States.
https lock icon
Secure .gov websites use HTTPS
A lock ( lock ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Explore Research Products in the PAR
It may take a few hours for recently added research products to appear in PAR search results.


Title: Comparison of click-capable oxaliplatin and cisplatin derivatives to better understand Pt(II)-induced nucleolar stress
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.  more » « less
Award ID(s):
2109255 2022168
PAR ID:
10473703
Author(s) / Creator(s):
; ; ; ; ;
Publisher / Repository:
Royal Society of Chemistry
Date Published:
Journal Name:
RSC Chemical Biology
Volume:
4
Issue:
10
ISSN:
2633-0679
Page Range / eLocation ID:
785 to 793
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. ; ; ; (, ChemBioChem)
    Abstract 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. 
    more » « less
  2. ; ; ; ; ; (, International Journal of Molecular Sciences)
    null (Ed.)
    Platinum coordination complexes have found wide applications as chemotherapeutic anticancer drugs in synchronous combination with radiation (chemoradiation) as well as precursors in focused electron beam induced deposition (FEBID) for nano-scale fabrication. In both applications, low-energy electrons (LEE) play an important role with regard to the fragmentation pathways. In the former case, the high-energy radiation applied creates an abundance of reactive photo- and secondary electrons that determine the reaction paths of the respective radiation sensitizers. In the latter case, low-energy secondary electrons determine the deposition chemistry. In this contribution, we present a combined experimental and theoretical study on the role of LEE interactions in the fragmentation of the Pt(II) coordination compound cis-PtBr2(CO)2. We discuss our results in conjunction with the widely used cancer therapeutic Pt(II) coordination compound cis-Pt(NH3)2Cl2 (cisplatin) and the carbonyl analog Pt(CO)2Cl2, and we show that efficient CO loss through dissociative electron attachment dominates the reactivity of these carbonyl complexes with low-energy electrons, while halogen loss through DEA dominates the reactivity of cis-Pt(NH3)2Cl2. 
    more » « less
  3. ; ; ; ; ; ; (, Dalton Transactions)
    null (Ed.)
    Combining strain-promoted azide–alkyne cycloaddition (SPAAC) and inorganic click (iClick) reactivity provides access to metal 1,2,3-triazolates. Experimental and computational insights demonstrate that iClick reactivity of the tested metal azides (LM-N 3 , M = Au, W, Re, Ru and Pt) depends on the accessibility of the azide functionality rather than electronic effects imparted by the metal. SPAAC iClick reactivity with cyclooctyne is observed when the azide functionality is sterically unencumbered, e.g. [Au(N 3 )(PPh 3 )] (Au–N3), [W(η 3 -allyl)(N 3 )(bpy)(CO) 2 ] (W–N3), and [Re(N 3 )(bpy)(CO) 3 ] [bpy = 2,2′-bipyridine] (Re–N3). Increased steric bulk and/or preequilibria with high activation barriers prevent SPAAC iClick reactivity for the complexes [Ru(N 3 )(Tp)(PPh 3 ) 2 ] [Tp = tris(pyrazolyl)borate] (Ru–N3), [Pt(N 3 )(CH 3 )(P i Pr 3 ) 2 ] [ i Pr = isopropyl] (Pt(II)–N3), and [Pt(N 3 )(CH 3 ) 3 ] 4 ((PtN3)4). Based on these computational insights, the SPAAC iClick reactivity of [Pt(N 3 )(CH 3 ) 3 (P(CH 3 ) 3 ) 2 ] (Pt(IV)–N3) was successfully predicted. 
    more » « less
  4. ; (, Organometallics)
    Isolable sulfonium-ylide stabilized palladium carbene complexes were synthesized through palladium(II)-induced cyclization of 1,2-alkynylarylsulfanes. X-ray crystallographic analysis characterized the maintenance of a palladium +2 oxidation state, with carbene-carbon–palladium bond lengths of 1.95 Å, indicating partial double bond character. These endocyclic sulfonium ylide carbenes represent the first characterized and/or isolable examples of this ligand class; such groups were previously proposed as reaction intermediates during cyclization–carbonylation reactions. A variety of palladium(II) complexes bearing sulfonium ylide carbene ligands, with differing substituents, were synthesized and the structure and stability of these complexes in solution were analyzed by 1H and 13C NMR spectroscopy, revealing reversibility and a stability dependence on substituents. The chirality of the sulfur heteroatom and the overall properties these ligands provide a potential electronic and steric alternative to existing carbene ligands, which could facilitate the future development of complementary metal-based reactivity. 
    more » « less
  5. ; ; ; ; ; ; ; ; (, Molecules)
    In this study, we report a novel platinum–doxorubicin conjugate that demonstrates superior therapeutic indices to cisplatin, doxorubicin, or their combination, which are commonly used in cancer treatment. This new molecular structure (1) was formed by conjugating an amphiphilic Pt(IV) prodrug of cisplatin with doxorubicin. Due to its amphiphilic nature, the Pt(IV)–doxorubicin conjugate effectively penetrates cell membranes, delivering both cisplatin and doxorubicin payloads intracellularly. The intracellular accumulation of these payloads was assessed using graphite furnace atomic absorption spectrometry and fluorescence imaging. Since the therapeutic effects of cisplatin and doxorubicin stem from their ability to target nuclear DNA, we hypothesized that the amphiphilic Pt(IV)–doxorubicin conjugate (1) would effectively induce nuclear DNA damage toward killing cancer cells. To test this hypothesis, we used flow the cytometric analysis of phosphorylated H2AX (γH2AX), a biomarker of nuclear DNA damage. The Pt(IV)–doxorubicin conjugate (1) markedly induced γH2AX in treated MDA-MB-231 breast cancer cells, showing higher levels than cells treated with either cisplatin or doxorubicin alone. Furthermore, MTT cell viability assays revealed that the enhanced DNA-damaging capability of complex 1 resulted in superior cytotoxicity and selectivity against human cancer cells compared to cisplatin, doxorubicin, or their combination. Overall, the development of this amphiphilic Pt(IV)–doxorubicin conjugate represents a new form of combination therapy with improved therapeutic efficacy. 
    more » « less
  • Citation Formats
  • MLA
  • APA
  • Chicago
  • BibTeX
  • Save / Share this Record
  • Send to Email