Anticancer potential of copper(i) complexes based on isopropyl ester derivatives of bis(pyrazol-1-yl)acetate ligands

Abstract

In this paper, the isopropyl ester derivatives LOiPr and L2OiPr of bis(pyrazol-1-yl)acetic acid and bis(3,5-dimethyl-pyrazol-1-yl)acetic acid were used as chelators for the preparation of new Cu(I) phosphane complexes 1–4. They were synthesized by the reaction of [Cu(CH3CN)4]PF6 and triphenylphosphine or 1,3,5-triaza-7-phosphaadamantane with LOiPr and L2OiPr ligands, in acetonitrile or acetonitrile/methanol solution. The authenticity of the compounds was confirmed by CHN analysis, 1H-, 13C- and 31P-NMR, FT-IR spectroscopy, and electrospray ionization mass spectrometry (ESI-MS). Furthermore, the electronic and molecular structures of the selected Cu(I) coordination compound 3 were investigated by synchrotron radiation-induced X-ray photoelectron spectroscopy (SR-XPS), and the local structure around the copper ion site was studied combining X-ray absorption fine structure (XAFS) spectroscopy techniques and DFT modelling. Triphenylphosphine as a coligand confers to [Cu(LOiPr)(PPh3)]PF6 (1) and [Cu(L2OiPr)(PPh3)]PF6 (3) a significant antitumor activity in 3D spheroidal models of human colon cancer cells. Investigations focused on the mechanism of action evidenced protein disulfide-isomerase (PDI) as an innovative molecular target for this class of phosphane copper(I) complexes. By hampering PDI activity, copper(I) complexes were able to cause an imbalance in cancer cell redox homeostasis thus leading to cancer cell death – a non-apoptotic programmed cell death.

Graphical abstract: Anticancer potential of copper(i) complexes based on isopropyl ester derivatives of bis(pyrazol-1-yl)acetate ligands

Supplementary files

Article information

Article type
Research Article
Submitted
07 Aug 2024
Accepted
07 Nov 2024
First published
13 Nov 2024
This article is Open Access
Creative Commons BY-NC license

RSC Med. Chem., 2025, Advance Article

Anticancer potential of copper(I) complexes based on isopropyl ester derivatives of bis(pyrazol-1-yl)acetate ligands

M. Pellei, C. Santini, M. Caviglia, J. Del Gobbo, C. Battocchio, C. Meneghini, S. Amatori, C. Donati, E. Zampieri, V. Gandin and C. Marzano, RSC Med. Chem., 2025, Advance Article , DOI: 10.1039/D4MD00610K

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