1. Synthesis and Cytotoxic Activity Evaluation of New Cu(I) Complexes of Bis(pyrazol-1-yl) Acetate Ligands Functionalized with an NMDA Receptor Antagonist.
- Author
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Pellei M, Bagnarelli L, Luciani L, Del Bello F, Giorgioni G, Piergentili A, Quaglia W, De Franco M, Gandin V, Marzano C, and Santini C
- Subjects
- Antineoplastic Agents chemical synthesis, Cell Line, Tumor, Cells, Cultured, Coordination Complexes chemical synthesis, Humans, Ligands, Molecular Structure, Acetates chemistry, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Coordination Complexes chemistry, Coordination Complexes pharmacology, Copper chemistry, Pyrazoles chemistry, Receptors, N-Methyl-D-Aspartate agonists
- Abstract
In the present article, copper(I) complexes of bis(pyrazol-1-yl) carboxylic acid (LH), bis(3,5-dimethylpyrazol-1-yl) carboxylic acid (L
2 H), and bis(pyrazol-1-yl) acetates conjugated with an N -methyl-d-aspartate (NMDA) receptor antagonist (LNMDA or L2NMDA ) and phosphane ligands (triphenylphosphine or 1,3,5-triaza-7-phosphaadamantane) were synthesized. The selection of an NMDA antagonist for the coupling with LH and L2 H was suggested by the observation that NMDA receptors are expressed and play a role in different types of cancer models. All the new complexes showed a significant antitumor activity on a panel of human tumor cell lines of different histology, with cisplatin-sensitive, cisplatin-resistant, or multi-drug-resistant phenotype. Their half maximal inhibitory concentration (IC50 ) values were in the low- and sub-micromolar range and, in general, significantly lower than that of cisplatin. Interestingly, the fact that all the complexes proved to be significantly more active than cisplatin even in three-dimensional (3D) spheroids of H157 and BxPC3 cancer cells increased the relevance of the in vitro results. Finally, morphological analysis revealed that the most representative complex 8 induced a massive swelling of the endoplasmic reticulum (ER) membrane, which is a clear sign of ER stress.- Published
- 2020
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