In Vitro Antitumor Activity of the Water Soluble Copper(I) Complexes Bearing the Tris(hydroxymethyl)phosphine Ligand

Monocationic hydrophilic complexes [Cu(thp)4]+ 3 and [Cu(bhpe)2]+ 4 were synthesized by ligand exchange reactions starting from the labile [Cu(CH3CN)4][PF6] precursor in the presence of an excess of the relevant hydrophilic phosphine. Complexes 3 and 4 were tested against a panel of several human tu...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2008-02, Vol.51 (4), p.798-808
Main Authors: Marzano, Cristina, Gandin, Valentina, Pellei, Maura, Colavito, Davide, Papini, Grazia, Lobbia, Giancarlo Gioia, Del Giudice, Elda, Porchia, Marina, Tisato, Francesco, Santini, Carlo
Format: Article
Language:English
Subjects:
Antineoplastic agents
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Biological and medical sciences
Cell Line, Tumor
Chelating Agents - chemical synthesis
Chelating Agents - chemistry
Copper
Drug Screening Assays, Antitumor
General aspects
Humans
Ligands
Medical sciences
Organometallic Compounds - chemical synthesis
Organometallic Compounds - chemistry
Organometallic Compounds - pharmacology
Organophosphorus Compounds - chemical synthesis
Organophosphorus Compounds - chemistry
Organophosphorus Compounds - pharmacology
Pharmacology. Drug treatments
Phosphines - chemical synthesis
Phosphines - chemistry
Phosphines - pharmacology
Solubility
Structure-Activity Relationship
Water
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Summary:Monocationic hydrophilic complexes [Cu(thp)4]+ 3 and [Cu(bhpe)2]+ 4 were synthesized by ligand exchange reactions starting from the labile [Cu(CH3CN)4][PF6] precursor in the presence of an excess of the relevant hydrophilic phosphine. Complexes 3 and 4 were tested against a panel of several human tumor cell lines. Complex 3 has been shown to be about 1 order of magnitude more cytotoxic than cisplatin. Chemosensitivity tests performed on cisplatin and multidrug resistance phenotypes suggested that complex 3 acts via a different mechanism of action than the reference drug. Different short-term proliferation assays suggested that lysosomal damage is an early cellular event associated with complex 3 cytotoxicity, probably mediated by an increased production of reactive oxygen species. Cytological stains and flow cytometric analyses indicated that the phosphine copper(I) complex is able to inhibit the growth of tumor cells via G2/M cell cycle arrest and paraptosis accompanied with the loss of mitochondrial transmembrane potential.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm701146c