In Vitro and in Vivo Anticancer Activity of Copper(I) Complexes with Homoscorpionate Tridentate Tris(pyrazolyl)borate and Auxiliary Monodentate Phosphine Ligands
journal contribution
posted on 2014-06-12, 00:00 authored by Valentina Gandin, Francesco Tisato, Alessandro Dolmella, Maura Pellei, Carlo Santini, Marco Giorgetti, Cristina Marzano, Marina PorchiaTetrahedral copper(I) TpCuP complexes 1–15, where Tp is a N,N,N-tris(azolyl)borate
and P is a tertiary phosphine, have been synthesized and characterized
by means of NMR, ESI-MS, and XAS-EXAFS, and X-ray diffraction analyses
on the representative complexes 1 and 10, respectively. All copper(I) complexes were evaluated for their
antiproliferative activity against a panel of human cancer cell lines
(including cisplatin and multidrug-resistant sublines). The two most
effective complexes [HB(pz)3]Cu(PCN), 1, and
[HB(pz)3]Cu(PTA), 2, showed selectivity toward
tumor vs normal cells, inhibition of 26S proteasome activity associated
with endoplasmic reticulum (ER) stress, and unfolded protein response
(UPR) activation. No biochemical hallmarks of apoptosis were detected,
and morphology studies revealed an extensive cytoplasmic vacuolization
coherently with a paraptosis-like cell death mechanism. Finally, the
antitumor efficacy of complex 1 was validated in the
murine Lewis Lung Carcinoma (LLC) model.
