Synthesis and Cytotoxicity Studies of Novel NHC*-Gold(I) Complexes Derived from Lepidiline A

Abstract

Ten novel N-heterocyclic carbene gold(I) complexes derived from lepidiline A (1,3-dibenzyl-4,5-dimethylimidazolium chloride) are reported here with full characterisation and biological testing. (1,3-Dibenzyl-4,5-diphenylimidazol-2-ylidene)gold(I) chloride (NHC*-AuCl) (1) was modified by substituting the chloride for the following: cyanide (2), dithiocarbamates (3–5), p-mercaptobenzoate derivatives (12–14) and N-acetyl-l-cysteine derivatives (15–17). All complexes were synthesised in good yields of 57–78%. Complexes 2, 12, 13, and 14 were further characterised by X-ray crystallography. Initial evaluation of the biological activity was conducted on all ten complexes against the multidrug resistant MCF-7topo breast cancer, HCT-116wt, and p53 knockout mutant HCT-116−/− colon carcinoma cell lines. Across the three cell lines tested, mainly single-digit micromolar IC50 values were observed. Nanomolar activity was exhibited on the MCF-7topo cell line with 3 displaying an IC50 of 0.28 μM ± 0.03 μM. Complexes incorporating a Au–S bond resulted in higher cytotoxic activity when compared to complexes 1 and 2. Theoretical calculations, carried out at the MN15/6–311++G(2df,p) computational level, show that NHC* is the more favourable ligand for Au(I)-Cl when compared to PPh3.

Synthesis, Selected Transformations, and Biological Activity of Alkoxy Analogues of Lepidilines A and C

“…In the pioneering work on the isolation of lepidilines A and B from a root extract of Lepidium meyenii , their metabolic activity was tested against several human cancer cell lines, and lepidiline B was found to be highly cytotoxic for some of them (bladder carcinoma UMUC3, pancreatic adenocarcinoma PACA2, breast carcinoma MDA231, and ovarian carcinoma FDIGROV) [ 12 ]. Later on, cytotoxicity of some lepidiline analogues [ 28 ], as well as metal complexes of nucleophilic carbenes (NHCs), derived from lepidilines or related imidazole-based structures, was also reported [ 29 , 30 , 31 ].…”

The Natural Product Lepidiline A as an N-Heterocyclic Carbene Ligand Precursor in Complexes of the Type [Ir(cod)(NHC)PPh3)]X: Synthesis, Characterisation, and Application in Hydrogen Isotope Exchange Catalysis

“…The natural product Lepidiline A 3•HCl is an imidazolium chloride salt, featuring two N-benzyl substituents, and methyl groups at the heterocycle's 4-and 5-positions [21] (Figure 2). We envisaged that this naturally-occurring imidazolium salt could serve as a vehicle to begin to explore the effect of steric and electronic changes in the NHC on the activity of our Ir(I) NHC/phosphine catalysts [22]. Iridium(I) complexes are amongst the most effective metal catalysts for directed HIE [10] and, in recent years, we have introduced a suite of highly active Ir(I) catalysts bearing a combination of bulky phosphine and N-heterocyclic carbene ligands ( Figure 1).…”

“…The natural product Lepidiline A 3•HCl is an imidazolium chloride salt, featuring two N-benzyl substituents, and methyl groups at the heterocycle's 4-and 5-positions [21] (Figure 2). We envisaged that this naturallyoccurring imidazolium salt could serve as a vehicle to begin to explore the effect of steric and electronic changes in the NHC on the activity of our Ir(I) NHC/phosphine catalysts [22]. Herein we report a study of the complexes 1a, 6a and 7, of the type [Ir(cod)(NHC)PPh3)]PF6 (cod = 1,5-cyclooctadiene), where the NHC ligand is IMes 4, IBn 5, or IBn Me 3, derived from Lepidiline A 3•HCl (Figure 3).…”

Gold as a Possible Alternative to Platinum-Based Chemotherapy for Colon Cancer Treatment

“…N-heterocyclic carbene gold(I) complexes 71–74 (Figure 5) derived from the natural compound lepidiline A (1,3-dibenzyl-4,5-dimethylimidazolium chloride), which displays anticancer properties, were reported by M. Tacke et al [97]. Theoretical studies pointed to the advantages of employing an NHC ligand, as opposed to a phosphine, since calculated Au–Cl bond distances revealed a shorter bond in the NHC*-AuCl compound, and therefore, one that is stronger than in the related phosphane compound.…”