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

In this paper, the isopropyl ester derivatives L^OiPr and L^2OiPr 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 L^OiPr and L^2OiPr 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(L^OiPr)(PPh₃)]PF₆ (1) and [Cu(L^2OiPr)(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.