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

Abstract

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 (LNMDA or L2NMDA) 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.

Anticancer Potency of Copper(I) Complexes Against a Range Cancer Cell Lines: A Review

“…3) against human pancreatic cancer; PSN-1, BxPC3, breast cancer; MCF-7, oral squamous; H157, skin cancer; A431, A431-Pt, ovarian cancer; A2780, A2780cis, A2780ADR reported higher anticancer potency (IC 50 0.01-5.9 μM) than that of their corresponding ligands and standard drug cisplatin (IC 50 0.45-26.7 μM). (Pellei et al, 2020) All the complexes exhibited very high cytotoxicity even in three dimensional (3D) cell culture of H157 (IC 50 2.7-13.0 μM) and BxPC3 (IC 50 1.2-10.2 μM) cancer cells compared with cisplatin against H157 (IC 50 52.51μM) and BxPC3 (IC 50 100.5 μM). The highest inhibitory effect by the complexes C 29 (IC 50 2.7 μM) and C 33 (IC 50 1.2μM) in 3D spheroid indicated that triphenyl phosphane and PTA have a large contribution to anticancer potency.…”

“…The highest inhibitory effect by the complexes C 29 (IC 50 2.7 μM) and C 33 (IC 50 1.2μM) in 3D spheroid indicated that triphenyl phosphane and PTA have a large contribution to anticancer potency. The ability of the complexes to cross the cellular plasmalemma resulted in the accumulation of copper in cancer cells showed a significant anticancer effect and overcome the cisplatin and multidrug resistance because they were able to slightly induce the DNA cleavage due to the limited generation of ROS (Pellei et al, 2020).…”

“…3. Copper(I) complexes of phosphane (triphenylphosphine, PPh 3 or 1,3,5-triaza-7phosphaadamantane, PTA) and bis(pyrazol-1-yl) acetate ligands functionalized with an N-methyl-daspartate (NMDA) receptor antagonist(Pellei et al, 2020)…”

Copper Coordination Compounds as Biologically Active Agents

“…Development of novel copper coordination compounds with antitumor activity is a promising and relevant area of medical chemistry [24][25][26][27]. A number of copper/Disulfiram-based drug combinations are in recruiting clinical trials as inexpensive and highly effective antitumor agents for metastatic breast cancer therapy and as diagnostic tools [28].…”

A New Dimeric Copper(II) Complex of Hexyl Bis(pyrazolyl)acetate Ligand as an Efficient Catalyst for Allylic Oxidations

“…Complexes containing κ 3 N,N,O-heteroscorpionate ligands, derived from bis(pyrazol-1-yl)acetates [ 40 , 41 , 42 ], are of particular interest due to their coordination behavior in organometallic chemistry [ 42 , 43 , 44 ], both as metalloenzyme models [ 42 , 45 , 46 , 47 , 48 ] and as starting reagents in the synthesis of bifunctional ligands and related metal complexes which are useful for their biological activity [ 49 , 50 , 51 , 52 , 53 , 54 ]. Furthermore, in the last years, interest in the catalytic activity of this type of metal complex has grown considerably [ 55 ].…”