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Bis(pyrazol-1-yl)acetic acid (HC(pz) 2 COOH) and bis(3,5-dimethyl-pyrazol-1-yl)acetic acid (HC(pz Me2 ) 2 COOH) were converted into the methyl ester derivatives 1 (L OMe ) and 2 (L 2OMe ), respectively, and were used for the preparation of silver(I) complexes 3 - 5 . The Ag(I) complexes were prepared by the reaction of AgNO 3 and 1,3,5-triaza-7-phosphaadamantane (PTA) or triphenylphosphine (PPh 3 ) with L OMe and L 2OMe in methanol solution. All Ag(I) complexes showed a significant in vitro antitumor activity, proving to be more effective than the reference drug cisplatin in the in-house human cancer cell line panel containing examples of different solid tumors. Compounds were particularly effective against the highly aggressive and intrinsically resistant human small-cell lung carcinoma (SCLC) cells, either in 2D and 3D cancer cell models. Mechanistic studies revealed their ability to accumulate into cancer cells and to selectively target Thioredoxin (TrxR), thus leading to redox homeostasis unbalance and ultimately inducing cancer cell death through apoptosis.

Bis(pyrazol-1-yl)acetic acid (HC(pz) 2 COOH) and bis(3,5-dimethyl-pyrazol-1-yl)acetic acid (HC(pz Me2 ) 2 COOH) were converted into the methyl ester derivatives 1 (L OMe ) and 2 (L 2OMe ), respectively, and were used for the preparation of Cu(I) and Cu(II) complexes 3 - 10 . The copper(II) complexes were prepared by the reaction of CuCl 2 ·2H 2 O or CuBr 2 with ligands 1 and 2 in methanol solution. The copper(I) complexes were prepared by the reaction of Cu[(CH 3 CN) 4 ]PF 6 and 1,3,5-triaza-7-phosphaadamantane (PTA) or triphenylphosphine with L OMe and L 2OMe in acetonitrile solution. Synchrotron radiation-based complementary techniques (XPS, NEXAFS, and XAS) were used to investigate the electronic and molecular structures of the complexes and the local structure around copper ions in selected Cu(I) and Cu(II) coordination compounds. All Cu(I) and Cu(II) complexes showed a significant in vitro antitumor activity, proving to be more effective than the reference drug cisplatin in a panel of human cancer cell lines, and were able to overcome cisplatin resistance. Noticeably, Cu complexes appeared much more effective than cisplatin in 3D spheroid cultures. Mechanistic studies revealed that the antitumor potential did not correlate with cellular accumulation but was consistent with intracellular targeting of PDI, ER stress, and paraptotic cell death induction.

Bis(pyrazol-1-yl)- and bis(3,5-dimethylpyrazol-1-yl)-acetates were conjugated with the 2-hydroxyethylester and 2-aminoethylamide derivatives of the antineoplastic drug lonidamine to prepare Cu(I) and Cu(II) complexes that might act through synergistic mechanisms of action due to the presence of lonidamine and copper in the same chemical entity. Synchrotron radiation-based complementary techniques [X-ray photorlectron spectroscopy and near-edge X-ray absorption fine structure (NEXAFS)] were used to characterize the electronic and molecular structures of the complexes and the local structure around the copper ion (XAFS) in selected complexes. All complexes showed significant antitumor activity, proving to be more effective than the reference drug cisplatin in a panel of human tumor cell lines, and were able to overcome oxaliplatin and multidrug resistance. Noticeably, these Cu complexes appeared much more effective than cisplatin against 3D spheroids of pancreatic PSN-1 cancer cells; among these, PPh 3 -containing Cu(I) complex 15 appeared to be the most promising derivative. Mechanistic studies revealed that 15 induced cancer cell death by means of an apoptosis-alternative cell death.

In the present article, copper(I) complexes of bis(pyrazol-1-yl) carboxylic acid (LH), bis(3,5-dimethylpyrazol-1-yl) carboxylic acid (L 2 H), and bis(pyrazol-1-yl) acetates conjugated with an N -methyl-d-aspartate (NMDA) receptor antagonist (L NMDA or L 2NMDA ) 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 L 2 H 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 (IC 50 ) 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.

Copper(II) complexes of bis(pyrazol-1-yl)- and bis(triazol-1-yl)-acetate heteroscorpionate ligands have been synthesized. The copper(II) complexes [HC(COOH)(pz Me2 ) 2 ]Cu[HC(COO)(pz Me2 ) 2 ]·ClO 4 , [HC(COOH)(pz) 2 ] 2 Cu(ClO 4 ) 2 (pz Me2 = 3,5-dimethylpyrazole; pz = pyrazole) were prepared by the reaction of Cu(ClO 4 ) 2 ·6H 2 O with bis(3,5-dimethylpyrazol-1-yl)acetic acid (HC(COOH)(pz Me2 ) 2 ) and bis(pyrazol-1-yl)acetic acid (HC(COOH)(pz) 2 ) ligands in ethanol solution. The copper(II) complex [HC(COOH)(tz) 2 ] 2 Cu(ClO 4 ) 2 ·CH 3 OH (tz = 1,2,4-triazole) was prepared by the reaction of Cu(ClO 4 ) 2 ·6H 2 O with bis(1,2,4-triazol-1-yl)acetic acid (HC(COOH)(tz) 2 ) ligand in methanol solution. The synthesized Cu(II) complexes, as well as the corresponding uncoordinated ligands, were evaluated for their cytotoxic activity in monolayer and 3D spheroid cancer cell cultures with different Pt(II)-sensitivity. The results showed that [HC(COOH)(pz Me2 ) 2 ]Cu[HC(COO)(pz Me2 ) 2 ]·ClO 4 was active against cancer cell lines derived from solid tumors at low IC 50 and this effect was retained in the spheroid model. Structure and ultra-structure changes of treated cancer cells analyzed by Transmission Electron Microscopy (TEM) highlighted the induction of a cytoplasmic vacuolization, thus suggesting paraptotic-like cancer cell death triggering.

Copper(I) and copper(II) complexes of 5-nitroimidazole conjugated heteroscorpionate ligands have been synthesized. In particular, the new 2,2-bis(pyrazol-1-yl)-N-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)acetamide ligand (L H MN) was synthesized by direct coupling of preformed side chain acid with 5-nitroimidazole and its coordination chemistry was investigated towards Cu(I) and Cu(II) acceptors and compared with that of the related 2,2-bis(3,5-dimethyl-1-H-pyrazol-1-yl)-N-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)acetamide ligand (L Me MN). The copper(II) complexes {[(L Me MN) 2 Cu]Cl 2 } and {[(L H MN) 2 Cu]Cl 2 } were prepared by the reaction of CuCl 2 ·2H 2 O with L H MN or L Me MN ligands in methanol solution. The water soluble copper(I) complexes {[(L Me MN)Cu(PTA) 2 ]}(PF 6 ) and {[(L H MN)Cu(PTA) 2 ]}(PF 6 ) were prepared by the reaction of Cu(CH 3 CN) 4 PF 6 and 1,3,5-triaza-7-phosphaadamantane (PTA) with L H MN or L Me MN ligands in acetonitrile solution. The new Cu(I) and Cu(II) complexes as well as the corresponding uncoordinated ligands were evaluated for their cytotoxic activity against 2D monolayer cultures of multiple human cancer cell lines and 3D-cultured HCT-15 colon cancer spheroids. Morphological analysis by Transmission Electron Microscopy (TEM) revealed the induction of a massive cytoplasmic vacuolization consistent with a paraptotic-like cancer cell death., (Copyright © 2018 Elsevier Inc. All rights reserved.)