Novel triazolium based 11^th group NHCs: synthesis, characterization and cellular response mechanisms

Abstract

The novel NHC ligand precursor 1,4-bis(4-nitrobenzyl)-1H-1,2,4-triazol-4-ium bromide, [HTz((pNO2Bz)2)]Br, has been synthesized and used in the synthesis of the corresponding metal complexes M[Tz((pNO2Bz)2)]Br (M = Cu(I), Ag(I) or Au(I)). These compounds were characterized by several spectroscopic techniques including NMR and mass spectroscopy. The complete series of Au(I), Ag(I) and Cu(I) 1,2,4-triazole based NHC complexes has been synthesized aiming at a SAR study and at identifying the primary cellular targets accounting for their cytotoxic action. The cytotoxic properties of the NHC complexes have been assessed in various human cancer cell lines, including cisplatin sensitive and resistant cells, the most efficacious antiproliferative compound being Cu(I)-NHC, which was able to promote a growth inhibitory effect up to ten times higher than that promoted by cisplatin. A detailed analysis of molecular and cellular pharmacology allowed us to elucidate the role of the metallic core in determining the biological properties. In particular, gold(I) and silver(I) NHC complexes were found to be able to hamper mammalian thioredoxin reductase (TrxR) activity in human A431 cervical cancer cells, ultimately leading to a dramatic alteration of the cellular redox state and to the induction of cell death via apoptosis. Conversely, the copper NHC complex was found to be capable of inhibiting proteasome functionality thus determining the induction of a non-apoptotic cell death pathway.

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.…”

“…[20][21][22][23][24][25][26] Copper and silver NHC complexes show a wide range of mechanisms of action, and further studies in this field are still ongoing. [27] In particular, although the interest in copper arises from the assumption that it is an essential element in the human body, [28][29][30] its anticancer potential has only recently been discovered and it appears to be promising for the development of a new class of therapeutics. [31][32][33][34][35][36] Water solubility has been an important goal in the development of metal complexes as therapeutic agents, [37][38][39][40][41][42] but in spite of the variety of NHC ligands available, [43] there is little literature related to watersoluble NHC complexes.…”

“…[31][32][33][34][35][36] Water solubility has been an important goal in the development of metal complexes as therapeutic agents, [37][38][39][40][41][42] but in spite of the variety of NHC ligands available, [43] there is little literature related to watersoluble NHC complexes. [27,39,[44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59] The poor aqueous solubility creates a pharmaceutical barrier for further pre-clinical and clinical evaluations; hence, the achievement of water solubility in NHC ligands, provided by the introduction of a hydrophilic moiety on the scaffold, such as P(O)(ONa) 2 , OH, NMe 3 + and PMe 3 + or sulfonate and carboxylate side chains, [39,[60][61][62] is useful for this purpose. [37] Among these groups, sulfonate has often been applied successfully.…”

Highly Electrophilic, Catalytically Active and Redox‐Responsive Cobaltoceniumyl and Ferrocenyl Triazolylidene Coinage Metal Complexes

“…In recent work, we could show that cobaltoceniumyl‐substituted metal complexes exhibit significant antitumor properties in various cancer cell lines, therefore, cobaltoceniumyl triazolylidene copper/silver/gold complexes are of obvious interest as potential metallodrugs in bioorganometallic chemistry. Currently, mostly standard NHC metal complexes are investigated in this area, only very few triazolylidene complexes have been studied so far . Below we present the first synthetic report of metal complexes based on cationic MIC (or NHC) ligands containing cobaltoceniumyl substituents.…”

Synthesis of Various Water Soluble and Stable Copper Complexes Bearing N‐Heterocyclic Carbene Ligands and Their Activity in DNA Alkylation

“…A variety of water-soluble NHCs have been prepared, [9,10] but rarely have the corresponding copper complexes. [11,12] In our hands, the most robust set of copper complexes are those described by the Gautier group. They have prepared a series of N-heterocyclic carbene copper complexes and used them in CuAAC reactions.…”