Elaborated study of Cu(II) carbosilane metallodendrimers bearing substituted iminopyridine moieties as antitumor agents.

Abstract

Iminopyridine-decorated carbosilane metallodendrimers have recently emerged as a promising strategy in the treatment of cancer diseases. Their unique features such as the nanometric size, the multivalent nature and the structural perfection offer an extraordinary platform to explore structure-to-property relationships. Herein, we showcase the outstanding impact on the antitumor activity of a parameter not explored before: the iminopyridine substituents in meta position. New Cu(II) carbosilane metallodendrimers, bearing methyl or methoxy substituents in the pyridine ring, were synthesized and thoroughly characterized. Electron Paramagnetic Resonance (EPR) was exploited to unveil the properties of the metallodendrimers. This study confirmed the presence of different coordination modes of the Cu(II) ion (Cu-N2O2, Cu-N4 and Cu-O4), whose ratios were determined by the structural features of the dendritic molecules. These metallodendrimers exhibited IC50 values in the low micromolar range (<6 μM) in tumor cell lines such as HeLa and MCF-7. The subsequent in vitro assays on both healthy (PBMC) and tumor (U937) myeloid cells revealed two key facts which improved the cytotoxicity and selectivity of the metallodrug: First, maximizing the Cu-N2O2 coordination mode; second, adequately selecting the pair ring-substituent/metal-counterion. The most promising candidates, G1(-CH3)Cl (8) and G1(-OCH3)NO3(17), exhibited a substantial increase in the antitumor activity in U937 tumor cells, compared to the non-substituted counterparts, probably through two different ROS-production pathways.

• Authors: Riccardo Carloni, Natalia Sanz Del Olmo, Barbara Canonico, Mariele Montanari, Caterina Ciacci, Gianluca Ambrosi, F Javier de la Mata, Maria Francesca Ottaviani, Sandra García-Gallego
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 215 Pg. 113292 (Apr 05 2021) ISSN: 1768-3254 [Electronic] France
• PMID: 33631696 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier Masson SAS. All rights reserved.

Chemical References

• Antineoplastic Agents
• Coordination Complexes
• Dendrimers
• Pyridines
• Reactive Oxygen Species
• Silanes
• Copper

Topics

• Antineoplastic Agents (chemical synthesis, pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Coordination Complexes (chemical synthesis, pharmacology)
• Copper (chemistry)
• Dendrimers (chemical synthesis, pharmacology)
• Drug Screening Assays, Antitumor
• Humans
• Leukocytes, Mononuclear (drug effects)
• Mitochondria (drug effects)
• Pyridines (chemical synthesis, pharmacology)
• Reactive Oxygen Species (metabolism)
• Silanes (chemical synthesis, pharmacology)