Breast Cancer Treatment: The Case of Gold(I)-Based Compounds as a Promising Class of Bioactive Molecules

Abstract

Breast cancers (BCs) may present dramatic diagnoses, both for ineffective therapies and for the limited outcomes in terms of lifespan. For these types of tumors, the search for new drugs is a primary necessity. It is widely recognized that gold compounds are highly active and extremely potent as anticancer agents against many cancer cell lines. The presence of the metal plays an essential role in the activation of the cytotoxicity of these coordination compounds, whose activity, if restricted to the ligands alone, would be non-existent. On the other hand, gold exhibits a complex biochemistry, substantially variable depending on the chemical environments around the central metal. In this review, the scientific findings of the last 6-7 years on two classes of gold(I) compounds, containing phosphane or carbene ligands, are reviewed. In addition to this class of Au(I) compounds, the recent developments in the application of Auranofin in regards to BCs are reported. Auranofin is a triethylphosphine-thiosugar compound that, being a drug approved by the FDA-therefore extensively studied-is an interesting lead gold compound and a good comparison to understand the activities of structurally related Au(I) compounds.

Keywords: Auranofin; IC50; breast cancer; carbene compounds; gold; in vitro; in vivo; metal-based drugs; molecular targets; phosphane compounds.

Scheme 1

The molecular structure of Auranofin.

Scheme 2

Representative structures of selected gold(I) phosphane compounds labeled as the entries of Table 1.

Scheme 2

Representative structures of selected gold(I) phosphane compounds labeled as the entries of Table 1.

Figure 1

Compounds 1 and 2 (4,5-dichloro-imidazolate-1yl-gold(I)-triphenylphosphane and 4,5-dicyano-imidazolate-1y-gold(I)-triphenylphosphane, respectively) suppressed breast cancer growth in vivo. FVB female mice were injected with syngeneic A17 TNBC cells and treated with cisplatin, compound 1 or 2, or isotonic solution. Treatment schedule (q3 × 4) started ten days after cell injection. (A) Tumor growth curves. Values are mean ± SEM, (5 mice/group). (B) Representative images of tumors explanted from control and treated mice at sacrifice (upper panel) and relative tumor weight (lower panel) 24 days after tumor challenge; values are mean ± SEM. The significance was determined by the one-way ANOVA test followed by Tukey’s multiple comparison post-test; each group was compared to control (* p < 0.05; *** p < 0.001). (C) Gold and platinum content in kidneys of mice treated with compound 1, compound 2, or cisplatin evaluated by inductively coupled plasma mass spectrometry (ICP-MS). The data are presented as micrograms of metal (Au or Pt) per gram of tissue. Values are mean ± SEM. The significance was determined by the one-way ANOVA test followed by Tukey’s multiple comparison test (*** p < 0.001) (modified from [38]).

Scheme 3

Representative structures of selected NHC gold(I) compounds: (A,B) mononuclear neutral compounds, (C,D) dinuclear neutral NHC compounds, (E) homoleptic cationic mononuclear compounds and (F) heteroleptic cationic mononuclear compounds. In the structures, R₁ = H, alkyl or Aryl and R₂ = alkyl or Aryl; R₃ and R₄ = H, Alkyl, Aryl; X = Anions, i.e., Halides; and L = neutral ligands, i.e., Triphenylphosphane.