In Vitroandin VivoAnticancer Activity of Copper(I) Complexes with Homoscorpionate Tridentate Tris(pyrazolyl)borate and Auxiliary Monodentate Phosphine Ligands

Abstract

Tetrahedral 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.

The first water‐soluble copper(I) complexes bearing sulfonated imidazole‐ and benzimidazole‐derived N‐heterocyclic carbenes: Synthesis and anticancer studies

“…These findings are in line with several results obtained for other series of copper(I) complexes, thus confirming that copper(I)–NHC complexes represent a promising class of copper complexes deserving further investigations aimed at the identification of new metal‐based anticancer drugs.…”

The first water‐soluble copper(I) complexes bearing sulfonated imidazole‐ and benzimidazole‐derived N‐heterocyclic carbenes: Synthesis and anticancer studies

“…These findings are in line with several results obtained for other series of copper(I) complexes, thus confirming that copper(I)–NHC complexes represent a promising class of copper complexes deserving further investigations aimed at the identification of new metal‐based anticancer drugs.…”

Copper(I)–Phosphine Polypyridyl Complexes: Synthesis, Characterization, DNA/HSA Binding Study, and Antiproliferative Activity

“…Furthermore, the studied complexes 1 – 5 also showed to be more active than cisplatin. Likewise, complexes 1 , 2 , 3 , and 5 displayed in vitro antitumor activity against cancers cell lines of lung (A549) and breast (MCF-7) similar to the ones reported for other Cu­(I)–tris­(hydroxy­methyl)­phosphine, Cu­(I)–phosphine polypyridyl, and Cu­(I)–phosphine tris­(pyrazolyl)­borate complexes . The IC 50 values found for complex 1 – 5 can be compared with those recently reported for Cu­(II) polypyridyl complexes in the same tumor cell A549, and another human lung cancer cell line (H-460), finding that all these copper­(I) complexes studied in this work, except complex 4 , showed better cytotoxic effects than the best Cu­(II) compound reported in those studies.…”

“…Likewise, complexes 1, 2, 3, and 5 displayed in vitro antitumor activity against cancers cell lines of lung (A549) and breast (MCF-7) similar to the ones reported for other Cu(I)−tris(hydroxymethyl)phosphine, 49 Cu(I)−phosphine polypyridyl, 50 and Cu-(I)−phosphine tris(pyrazolyl)borate complexes. 51 The IC 50 values found for complex 1−5 can be compared with those recently reported for Cu(II) polypyridyl complexes in the same tumor cell A549, 11 and another human lung cancer cell line (H-460), 52 finding that all these copper(I) complexes studied in this work, except complex 4, showed better cytotoxic effects than the best Cu(II) compound reported in those studies. The cytotoxicity toward tumor cells lines, exhibited by complexes 1−5, indicated that the coordination of both phosphine and polypyridyl chelating ligands in one single molecule made it possible to create copper(I) complexes with an increased antitumor activity.…”

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

“…In order to characterize the cellular morphological changes induced by the copper(I) compounds, we observed BxPC3 cancer cells treated for 24 h with IC 50 concentrations of the most representative compound 8 by using TEM. Analogously to what was observed with other Cu(I) complexes [17,20], morphological analysis revealed that 8 induced a massive swelling of the endoplasmic reticulum (ER) membrane, which is a clear sign of ER stress (Figure 4, panel B, c). In addition, at 48 h of treatment, clear mitophagic signs of mitochondria damage and mitophagy induction were evident (Figure 4, panel B, d).…”

The first water‐soluble copper(I) complexes bearing sulfonated imidazole‐ and benzimidazole‐derived N‐heterocyclic carbenes: Synthesis and anticancer studies

“…These findings are in line with several results obtained for other series of copper(I) complexes, thus confirming that copper(I)–NHC complexes represent a promising class of copper complexes deserving further investigations aimed at the identification of new metal‐based anticancer drugs.…”

Copper(I)–Phosphine Polypyridyl Complexes: Synthesis, Characterization, DNA/HSA Binding Study, and Antiproliferative Activity

“…Furthermore, the studied complexes 1 – 5 also showed to be more active than cisplatin. Likewise, complexes 1 , 2 , 3 , and 5 displayed in vitro antitumor activity against cancers cell lines of lung (A549) and breast (MCF-7) similar to the ones reported for other Cu­(I)–tris­(hydroxy­methyl)­phosphine, Cu­(I)–phosphine polypyridyl, and Cu­(I)–phosphine tris­(pyrazolyl)­borate complexes . The IC 50 values found for complex 1 – 5 can be compared with those recently reported for Cu­(II) polypyridyl complexes in the same tumor cell A549, and another human lung cancer cell line (H-460), finding that all these copper­(I) complexes studied in this work, except complex 4 , showed better cytotoxic effects than the best Cu­(II) compound reported in those studies.…”

“…Likewise, complexes 1, 2, 3, and 5 displayed in vitro antitumor activity against cancers cell lines of lung (A549) and breast (MCF-7) similar to the ones reported for other Cu(I)−tris(hydroxymethyl)phosphine, 49 Cu(I)−phosphine polypyridyl, 50 and Cu-(I)−phosphine tris(pyrazolyl)borate complexes. 51 The IC 50 values found for complex 1−5 can be compared with those recently reported for Cu(II) polypyridyl complexes in the same tumor cell A549, 11 and another human lung cancer cell line (H-460), 52 finding that all these copper(I) complexes studied in this work, except complex 4, showed better cytotoxic effects than the best Cu(II) compound reported in those studies. The cytotoxicity toward tumor cells lines, exhibited by complexes 1−5, indicated that the coordination of both phosphine and polypyridyl chelating ligands in one single molecule made it possible to create copper(I) complexes with an increased antitumor activity.…”

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

“…In order to characterize the cellular morphological changes induced by the copper(I) compounds, we observed BxPC3 cancer cells treated for 24 h with IC 50 concentrations of the most representative compound 8 by using TEM. Analogously to what was observed with other Cu(I) complexes [17,20], morphological analysis revealed that 8 induced a massive swelling of the endoplasmic reticulum (ER) membrane, which is a clear sign of ER stress (Figure 4, panel B, c). In addition, at 48 h of treatment, clear mitophagic signs of mitochondria damage and mitophagy induction were evident (Figure 4, panel B, d).…”

The first water‐soluble copper(I) complexes bearing sulfonated imidazole‐ and benzimidazole‐derived N‐heterocyclic carbenes: Synthesis and anticancer studies

“…These findings are in line with several results obtained for other series of copper(I) complexes, thus confirming that copper(I)–NHC complexes represent a promising class of copper complexes deserving further investigations aimed at the identification of new metal‐based anticancer drugs.…”

Copper(I)–Phosphine Polypyridyl Complexes: Synthesis, Characterization, DNA/HSA Binding Study, and Antiproliferative Activity

“…Furthermore, the studied complexes 1 – 5 also showed to be more active than cisplatin. Likewise, complexes 1 , 2 , 3 , and 5 displayed in vitro antitumor activity against cancers cell lines of lung (A549) and breast (MCF-7) similar to the ones reported for other Cu­(I)–tris­(hydroxy­methyl)­phosphine, Cu­(I)–phosphine polypyridyl, and Cu­(I)–phosphine tris­(pyrazolyl)­borate complexes . The IC 50 values found for complex 1 – 5 can be compared with those recently reported for Cu­(II) polypyridyl complexes in the same tumor cell A549, and another human lung cancer cell line (H-460), finding that all these copper­(I) complexes studied in this work, except complex 4 , showed better cytotoxic effects than the best Cu­(II) compound reported in those studies.…”

“…Likewise, complexes 1, 2, 3, and 5 displayed in vitro antitumor activity against cancers cell lines of lung (A549) and breast (MCF-7) similar to the ones reported for other Cu(I)−tris(hydroxymethyl)phosphine, 49 Cu(I)−phosphine polypyridyl, 50 and Cu-(I)−phosphine tris(pyrazolyl)borate complexes. 51 The IC 50 values found for complex 1−5 can be compared with those recently reported for Cu(II) polypyridyl complexes in the same tumor cell A549, 11 and another human lung cancer cell line (H-460), 52 finding that all these copper(I) complexes studied in this work, except complex 4, showed better cytotoxic effects than the best Cu(II) compound reported in those studies. The cytotoxicity toward tumor cells lines, exhibited by complexes 1−5, indicated that the coordination of both phosphine and polypyridyl chelating ligands in one single molecule made it possible to create copper(I) complexes with an increased antitumor activity.…”

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

“…In order to characterize the cellular morphological changes induced by the copper(I) compounds, we observed BxPC3 cancer cells treated for 24 h with IC 50 concentrations of the most representative compound 8 by using TEM. Analogously to what was observed with other Cu(I) complexes [17,20], morphological analysis revealed that 8 induced a massive swelling of the endoplasmic reticulum (ER) membrane, which is a clear sign of ER stress (Figure 4, panel B, c). In addition, at 48 h of treatment, clear mitophagic signs of mitochondria damage and mitophagy induction were evident (Figure 4, panel B, d).…”