Palladium(II)-Indenyl Complexes Bearing N-Heterocyclic Carbene (NHC) Ligands as Potent and Selective Metallodrugs toward High-Grade Serous Ovarian Cancer Models
In this study, we synthesized novel Pd(II)-indenyl complexes using various <i>N</i>-heterocyclic carbene (NHC) ligands, including chelating NHC-picolyl, NHC-thioether, and diNHC ligands, and two monodentate NHCs. Transmetalation reactions between a Pd(II)-indenyl precursor and silver-NHC complexes were generally employed, except for chelating diNHC derivatives, which required direct reaction with bisimidazolium salts and potassium carbonate. Characterization included NMR, HRMS analysis, and single-crystal X-ray diffraction. <i>In vitro</i> on five ovarian cancer cell lines showed notable cytotoxicity, with IC<sub>50</sub> values in the micro- and submicromolar range. Some compounds exhibited intriguing selectivity for cancer cells due to higher tumor cell uptake. Mechanistic studies revealed that monodentate NHCs induced mitochondrial damage while chelating ligands caused DNA damage. One chelating NHC-picolyl ligand showed promising cytotoxicity and selectivity in high-grade serous ovarian cancer models, supporting its consideration for preclinical study.
Authors
- Vincenzo Canzonieri (ORCID: https://orcid.org/0000-0001-6010-0976)
- Urška Kamenšek (ORCID: https://orcid.org/0000-0002-0481-4226)
- Enrica Bortolamiol (ORCID: https://orcid.org/0000-0002-1199-9839)
- Flavio Rizzolio (ORCID: https://orcid.org/0000-0002-3400-4363)
- Thomas Scattolin (ORCID: https://orcid.org/0000-0001-7345-9670)
- Simona Kranjc (ORCID: https://orcid.org/0000-0003-0538-7841)
- Maja Čemažar (ORCID: https://orcid.org/0000-0002-1418-1928)
- Fabiano Visentin (ORCID: https://orcid.org/0000-0001-9513-1182)
- Enrico Cavarzerani (ORCID: https://orcid.org/0000-0001-9322-0878)
- Valentina Gandin (ORCID: https://orcid.org/0000-0003-0442-0670)
- Nicola Demitri (ORCID: https://orcid.org/0000-0003-0288-3233)
- Matteo Mauceri (ORCID: https://orcid.org/0000-0002-5299-994X)
- Rachele Piccolo
- Chiara Donati (ORCID: https://orcid.org/0009-0009-0163-5730)
Institutions
- University of Padua (IT)
- University of Trieste (IT)
- Ca' Foscari University of Venice (IT)
- Elettra-Sincrotrone Trieste S.C.p.A. (IT)
- Institute of Oncology Ljubljana (SI)
- Centro di Riferimento Oncologico (IT)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-08-09
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01203
- Citations
- 8
- Primary Topic
- N-Heterocyclic Carbenes in Organic and Inorganic Chemistry
- Type
- article
- Field-Weighted Citation Impact
- 2.00
Funders
- Ministero della Salute
- Javna Agencija za Raziskovalno Dejavnost RS
- Associazione Italiana per la Ricerca sul Cancro