Synthesis and Cytotoxic Activity Evaluation of New Cu(I) Complexes of Bis(pyrazol-1-yl) Acetate Ligands Functionalized with an NMDA Receptor Antagonist.

Maura Pellei,Valentina Gandin,Alessandro Piergentili,Luca Bagnarelli,Cristina Marzano,Carlo Santini,Lorenzo Luciani,Michele De Franco,Fabio Del Bello,Wilma Quaglia,Gianfabio Giorgioni

doi:10.3390/ijms21072616

Maura Pellei, Valentina Gandin + Show 9 more

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https://doi.org/10.3390/ijms21072616

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Abstract

In the present article, copper(I) complexes of bis(pyrazol-1-yl) carboxylic acid (LH), bis(3,5-dimethylpyrazol-1-yl) carboxylic acid (L2H), 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 L2H 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.

Highlights

Copper complexes are emerging as metal-based drug candidates for the treatment of cancer, due to their wide structural variability, biologically accessible redox properties, and bioavailability [1,2,3,4]
In the present article, copper(I) complexes of bis(pyrazol-1-yl) carboxylic acid (LH), bis(3,5-dimethylpyrazol-1-yl) carboxylic acid (L2H), and bis(pyrazol-1-yl) acetates conjugated with an N-methyl-d-aspartate (NMDA) receptor antagonist (LNMDA or L2NMDA) and phosphane ligands were synthesized
We recently reported that Cu(II) complexes of bifunctional heteroscorpionate ligands (LNMDA and L2NMDA, Scheme 1), obtained by conjugating bis(pyrazolyl) carboxylic acid (LH) and bis(3,5-dimethylpyrazolyl) carboxylic acid (L2H) with the NMDA receptor antagonist 6,6-diphenyl-1,4-dioxan-2-yl) methanamine [44], showed antiproliferative activity against a panel of human tumor cell lines

Summary

Introduction

Copper complexes are emerging as metal-based drug candidates for the treatment of cancer, due to their wide structural variability, biologically accessible redox properties, and bioavailability [1,2,3,4]. Part of this interest stems from the assumption that endogenous metal ions are less toxic to normal cells than non-endogenous metals. There is increasing evidence that the mechanism of action of copper complexes is distinctly different from that of Pt-based compounds, such as cisplatin [9] and, they might represent efficacious alternatives to platinum-based drugs [3,10]

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