In the present article, copper(I) complexes of bis(pyrazol-1-yl) carboxylic acid (LH), bis(3,5-dimethylpyrazol-1-yl) carboxylic acid (L²H), 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 L²H 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 (IC₅₀) 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]·ClO₄, [HC(COOH)(pz)₂]₂Cu(ClO₄)₂ (pz^Me2 = 3,5-dimethylpyrazole; pz = pyrazole) were prepared by the reaction of Cu(ClO₄)₂·6H₂O 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]₂Cu(ClO₄)₂·CH₃OH (tz = 1,2,4-triazole) was prepared by the reaction of Cu(ClO₄)₂·6H₂O 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]·ClO₄ was active against cancer cell lines derived from solid tumors at low IC₅₀ 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.

Bis(pyrazol-1-yl)acetic acid (HC(pz)₂COOH) and bis(3,5-dimethyl-pyrazol-1-yl)acetic acid (HC(pz^Me2)₂COOH) 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 CuCl₂·2H₂O or CuBr₂ with ligands 1 and 2 in methanol solution. The copper(I) complexes were prepared by the reaction of Cu[(CH₃CN)₄]PF₆ 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)acetic acid (HC(pz)₂COOH) and bis(3,5-dimethyl-pyrazol-1-yl)acetic acid (HC(pz^Me2)₂COOH) 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 AgNO₃ and 1,3,5-triaza-7-phosphaadamantane (PTA) or triphenylphosphine (PPh₃) 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.

A new dimeric copper(II) bromide complex, [Cu(L^OHex)Br(μ-Br)]₂ (1), was prepared by a reaction of CuBr₂ with the hexyl bis(pyrazol-1-yl)acetate ligand (L^OHex) in acetonitrile solution and fully characterized in the solid state and in solution. The crystal structure of 1 was also determined: the complex is interlinked by two bridging bromide ligands and possesses terminal bromide ligands on each copper atom. The two pyrazolyl ligands in 1 coordinate with the nitrogen atoms to complete the Cu coordination sphere, resulting in a five-coordinated geometry—away from idealized trigonal bipyramidal and square pyramidal geometries—which can better be described as distorted square pyramidal, as measured by the τ and χ structural parameters. The pendant hexyloxy chain is disordered over two arrangements, with final site occupancies refined to 0.705 and 0.295. The newly synthesized complex was evaluated as a catalyst in copper-catalyzed C–H oxidation for allylic functionalization through a Kharasch–Sosnovsky reaction without any external reducing agent. Using 0.5 mol% of this catalyst, and tert-butyl peroxybenzoate (Luperox) as an oxidant, allylic benzoates were obtained with up to 90% yield. The general reaction time was only slightly decreased to 24 h but a very significant decrease in the alkene:Luperox ratio to 3:1 was achieved. These factors show relevant improvements with respect to classical Kharasch–Sosnovsky reactions in terms of rate and amount of reagents. The present study highlights the potential of copper(II) complexes containing functionalized bis(pyrazol-1-yl)acetate ligands as efficient catalysts for allylic oxidations.

In this study, four new N-(alkyl/aryl)imidazolium-borates were prepared, and their deprotonation reactions were investigated. Addition of BH₃•THF to N-benzylimidazoles and N-mesitylimidazoles leads to imidazolium-trihydridoborate adducts. Ammonium tetraphenylborate reacts with benzyl- or mesityl-imidazoles with the loss of one of the phenyl groups yielding the corresponding imidazolium-triphenylborates. Their authenticity was confirmed by CHN analysis, ¹H-NMR, ¹³C-NMR, ¹¹B-NMR, FT-IR spectroscopy, and electrospray ionization mass spectrometry (ESI-MS). 3-Benzyl-imidazolium-1-yl)trihydridoborate, (HIm^Bn)BH₃, and (3-mesityl-imidazolium-1-yl)trihydridoborate, (HIm^Mes)BH₃, were also characterized by X-ray crystallography. The reactivity of these new compounds as carbene precursors in an effort to obtain borate-NHC complexes was investigated and a new carbene-borate adduct (which dimerizes) was obtained via a microwave-assisted procedure.