Organoiridium Complexes: Anticancer Agents and Catalysts

Abstract

ConspectusIridium is a relatively rare precious heavy metal, only slightly less dense than osmium. Researchers have long recognized the catalytic properties of square-planar IrI complexes, such as Crabtree’s hydrogenation catalyst, an organometallic complex with cyclooctadiene, phosphane, and pyridine ligands. More recently, chemists have developed half-sandwich pseudo-octahedral pentamethylcyclopentadienyl IrIII complexes containing diamine ligands that efficiently catalyze transfer hydrogenation reactions of ketones and aldehydes in water using H2 or formate as the hydrogen source. Although sometimes assumed to be chemically inert, the reactivity of low-spin 5d6 IrIII centers is highly dependent on the set of ligands. Cp* complexes with strong σ-donor C∧C-chelating ligands can even stabilize IrIV and catalyze the oxidation of water. In comparison with well developed Ir catalysts, Ir-based pharmaceuticals are still in their infancy. In this Account, we review recent developments in organoiridium complexes as both catalysts and anticancer agents.Initial studies of anticancer activity with organoiridium complexes focused on square-planar IrI complexes because of their structural and electronic similarity to PtII anticancer complexes such as cisplatin. Recently, researchers have studied half-sandwich IrIII anticancer complexes. These complexes with the formula [(Cpx)Ir(L∧L′)Z]0/n+ (with Cp* or extended Cp* and L∧L′ = chelated C∧N or N∧N ligands) have a much greater potency (nanomolar) toward a range of cancer cells (especially leukemia, colon cancer, breast cancer, prostate cancer, and melanoma) than cisplatin. Their mechanism of action may involve both an attack on DNA and a perturbation of the redox status of cells. Some of these complexes can form IrIII-hydride complexes using coenzyme NAD(P)H as a source of hydride to catalyze the generation of H2 or the reduction of quinones to semiquinones. Intriguingly, relatively unreactive organoiridium complexes containing an imine as a monodentate ligand have prooxidant activity, which appears to involve catalytic hydride transfer to oxygen and the generation of hydrogen peroxide in cells. In addition, researchers have designed inert IrIII complexes as potent kinase inhibitors. Octahedral cyclometalated IrIII complexes not only serve as cell imaging agents, but can also inhibit tumor necrosis factor α, promote DNA oxidation, generate singlet oxygen when photoactivated, and exhibit good anticancer activity. Although relatively unexplored, organoiridium chemistry offers unique features that researchers can exploit to generate novel diagnostic agents and drugs with new mechanisms of action.

Pharmaco-genomic investigations of organo-iridium anticancer complexes reveal novel mechanism of action

“…9,10 Here we report the results of phenotypic screening and in-depth MoA profiling of two organo-iridium(III) complexes ( These studies point to a unique MoA for organo-iridium complexes with little in common with previously-screened agents, except organo-osmium complexes.…”

The development of anticancer ruthenium(ii) complexes: from single molecule compounds to nanomaterials

“…In this regard, metal complexes hold potential as novel anticancer agents against a wide majority of cancer types. 1–7 Cisplatin or cis-diamminedichloroplatinum(II) is the most widely known metal-based anticancer drug. Cisplatin has been shown to have efficacy against lung, head, ovarian, neck, and esophageal cancers.…”

Evaluation of Perylene Bisimide‐Based RuII and IrIII Complexes as Photosensitizers for Photodynamic Therapy

“…[46] Nevertheless, several Ir III compounds, most commonly bearing cyclometalated ligands, have recently been found to be promising PDT agents. [46][47][48][49][50][51][52] Figure 1. Structures of TLD-1433, a PS in clinical trial as a PDT PS, and complexes 1 and 2 with their respective ligands L1 and L2 studied in this paper.…”