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Dinuclear gold(I) complexes based on carbene and diphosphane ligands: bis[2-(dicyclohexylphosphano)ethyl]amine complex inhibits the proteasome activity, decreases stem cell markers and spheroid viability in lung cancer cells

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Abstract

Three new dinuclear gold(I) complexes (1–3) containing a carbene (1,3-Bis(2,6-di-isopropylphenyl)imidazol-2-ylidene (IPr)) and diphosphane ligands [bis(1,2-diphenylphosphano)ethane (Dppe), bis(1,3-diphenylphosphano)propane (Dppp) and bis[2-(dicyclohexylphosphano)ethyl]amine (DCyPA)], were synthesized and characterized by elemental analysis and, ESI–MS, mid FT-IR and NMR spectroscopic methods. The structures of complexes 2 and 3 were determined by X-ray crystallography, which revealed that the complexes are dinuclear having gold(I) ions linearly coordinated. The anticancer activities of the complexes (1–3) were evaluated in lung (A549), breast (MC-F7), prostate (PC-3), osteosarcoma (MG-63) and ovarian (A2780 and A2780cis) cancer models. Growth inhibition by the new complexes was higher than cisplatin in all cell lines tested. The mechanism of action of complex 3 was investigated in A549 cells using 2-dimensional (2D) models and 3D-multicellular tumor spheroids. Treatment of A549 cells with complex 3 caused: the induction of apoptosis and the generation of reactive oxygen species; the cell cycle arrest in the G0/G1 phase; the inhibition of both the proteasome and the NF-kB activity; the down-regulation of lung cancer stem cell markers (NOTCH1, CD133, ALDH1 and CD44). Complex 3 was more active than cisplatin also in 3D models of A549 lung cancer cells.

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The authors greatly appreciate and thank the financial support provided by King Fahd University of Petroleum and Minerals, Interdisciplinary Research Center for Advanced Materials under the project No. INAM2210 (A.A. Isab). This work was supported in part by grant IG 15844 from the Italian Association for Cancer Research (D.A.) and Italian Ministry of Health (Ricerca Corrente).

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Author notes

  1. Naike Casagrande, Cinzia Borghese and Adam A. A. Sulaiman were contributed equally to this work.

Authors and Affiliations

  1. Molecular Oncology, Centro Di Riferimento Oncologico Di Aviano (CRO) IRCCS, 33081, Aviano, Italy

    Naike Casagrande, Cinzia Borghese & Donatella Aldinucci

  2. Immunopathology and Cancer Biomarkers Unit, Centro Di Riferimento Oncologico Di Aviano (CRO), IRCCS, 33081, Aviano, Italy

    Giuseppe Corona

  3. Department of Chemistry, Government College University Lahore, Lahore, 54000, Pakistan

    Muhammad Altaf

  4. Core Research Facilities (CRF), King Fahd University of Petroleum and Minerals, 31261, Dhahran, Saudi Arabia

    Adam A. A. Sulaiman

  5. Department of Chemistry, King Fahd University of Petroleum and Minerals, 31261, Dhahran, Saudi Arabia

    Adam A. A. Sulaiman, Anvarhusein A. Isab & Abdul Malik P. Peedikakkal

  6. Interdisciplinary Research Center for Advanced Materials, King Fahd University of Petroleum and Minerals, 31261, Dhahran, Saudi Arabia

    Anvarhusein A. Isab

  7. Department of Chemistry, College of Sciences and Humanities, Prince Sattam Bin Abdulaziz University, 11942, Al-Kharj, Saudi Arabia

    Saeed Ahmad

  8. Interdisciplinary Research Center for Hydrogen and Energy Storage, King Fahd University of Petroleum and Minerals, 31261, Dhahran, Saudi Arabia

    Abdul Malik P. Peedikakkal

Authors
  1. Naike Casagrande
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  2. Cinzia Borghese
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  3. Giuseppe Corona
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  4. Donatella Aldinucci
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  5. Muhammad Altaf
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  6. Adam A. A. Sulaiman
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  7. Anvarhusein A. Isab
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  9. Abdul Malik P. Peedikakkal
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Contributions

N.C: Investigation, Methodology, Writing – review and editing; C.B.: Methodology, Formal analysis; G.C.: Methodology, Data acquisition; D. A.: Investigation, Supervision, Writing—original draft; M.A.: Investigation, Validation; A.A.A. S.: Investigation, Methodology, Formal analysis; A.A.I.: Project administration, Supervision; S.A.: Investigation, Writing—original draft; A.M.P.P.: Formal analysis, Software.

Corresponding authors

Correspondence to Donatella Aldinucci, Adam A. A. Sulaiman or Anvarhusein A. Isab.

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Supplementary Information

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775_2023_2025_MOESM1_ESM.pdf

Supplementary file1 (PDF 818 KB) Crystallographic data of complexes 2 and 3 have been deposited with the Cambridge Crystallographic Data Centre via the CCDC Number 2251701 and 2251702 respectively. Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, e-mail: deposit@ccdc.cam.ac.uk or www.ccdc.cam.ac.uk.

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Casagrande, N., Borghese, C., Corona, G. et al. Dinuclear gold(I) complexes based on carbene and diphosphane ligands: bis[2-(dicyclohexylphosphano)ethyl]amine complex inhibits the proteasome activity, decreases stem cell markers and spheroid viability in lung cancer cells. J Biol Inorg Chem 28, 751–766 (2023). https://doi.org/10.1007/s00775-023-02025-x

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  • DOI: https://doi.org/10.1007/s00775-023-02025-x

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