A Comparative Analysis of the In Vitro Anticancer Activity of Iridium(III) {η5-C5Me4R} Complexes with Variable R Groups

Abstract

Piano-stool iridium complexes based on the pentamethylcyclopentadienyl ligand (Cp*) have been intensively investigated as anticancer drug candidates and hold much promise in this setting. A systematic study aimed at outlining the effect of Cp* mono-derivatization on the antiproliferative activity is presented here. Thus, the dinuclear complexes [Ir(η5-C5Me4R)Cl(μ-Cl)]2 (R = Me, 1a; R = H, 1b; R = Pr, 1c; R = 4-C6H4F, 1d; R = 4-C6H4OH, 1e), their 2-phenylpyridyl mononuclear derivatives [Ir(η5-C5Me4R)(kN,kCPhPy)Cl] (2a–d), and the dimethylsulfoxide complex [Ir{η5-C5Me4(4-C6H4OH)}Cl2(κS-Me2S=O)] (3) were synthesized, structurally characterized, and assessed for their cytotoxicity towards a panel of six human and rodent cancer cell lines (mouse melanoma, B16; rat glioma, C6; breast adenocarcinoma, MCF-7; colorectal carcinoma, SW620 and HCT116; ovarian carcinoma, A2780) and one primary, human fetal lung fibroblast cell line (MRC5). Complexes 2b (R = H) and 2d (4-C6H4F) emerged as the most active ones and were selected for further investigation. They did not affect the viability of primary mouse peritoneal cells, and their tumoricidal action arises from the combined influence on cellular proliferation, apoptosis and senescence. The latter is triggered by mitochondrial failure and production of reactive oxygen and nitrogen species.

The Role of Metallodrugs in Cellular Senescence

“…The last example that has been published of a metal complex able to generated senescence was reported by Maksimovic-Ivanic and Marchetti in 2021. [60] These authors described two samples of Ir III complexes, 13 and 14, which have cytotoxicity in six different human and rodent cell lines within a wide range of concentrations (IC 50 values between 37-1.2 μM), Figure 8A. Studies made on A2780 cells (ovarian cancer cell line), showed that both complexes follow an apoptotic cell death mechanism by activation of caspases.…”

Necrosis-Inducing High-Valent Oxo–Rhenium(V) Complexes with Potent Antitumor Activity: Synthesis, Aquation Chemistry, Cisplatin Cross-Resistance Profile, and Mechanism of Action

“…Formation of an aqua complex (M−OH 2 ) through the exchange of the "Cl" ligand with water is considered an important activation step for anticancer metal complexes containing M−Cl bond(s). 4,11,12 A few previous reports also showed the hydrolysis of the Re−Cl bond in [(N ∧ N)(CO) 3 Re I Cl] type anticancer complexes in aqueous media. 15,39 However, aquation chemistries of Re-(V)�O anticancer complexes including Re-1, Re-2, and Re-3 (Figure 1) remain unexplored.…”

“…Innate and acquired resistance against Pt drugs increasingly reduce their efficacy, leading to treatment failure . Further, severe side effects, such as nephrotoxicity, neurotoxicity, myelosuppression, etc., arising from the indiscriminate killing of cancer and normal cells, limit their applicability as well as dose escalation during the treatment cycle. , To overcome these limitations, tremendous efforts have been devoted toward the development of non-Pt metal-based drugs with a mechanism of action different from the DNA-targeted Pt drugs, and promising results were obtained using ruthenium (Ru), gold (Au), iridium (Ir), and rhenium (Re) complexes. − …”

Metallodrugs: Mechanisms of Action, Molecular Targets and Biological Activity

“…Four manuscripts submitted for this Special Issue report new data on the cytotoxic and potential antitumor actions of Pt(II), Fe(III), Cu(II), Zn(II) and Ir(III) compounds [ 10 , 11 , 12 , 13 ].…”

“…In the paper by Marchetti and coworkers, the in vitro anticancer activity of piano stool mononuclear and binuclear Ir(III) complexes based on the pentamethylcyclopentadienyl ligand (Cp*) was evaluated [ 11 ]. Various compounds were synthetized, characterized and assessed for their cytotoxicity against six human and rodent cancer cell lines.…”