Targets, Mechanisms and Cytotoxicity of Half-Sandwich Ir(III) Complexes Are Modulated by Structural Modifications on the Benzazole Ancillary Ligand

Abstract

Cancers are driven by multiple genetic mutations but evolve to evade treatments targeting specific mutations. Nonetheless, cancers cannot evade a treatment that targets mitochondria, which are essential for tumor progression. Iridium complexes have shown anticancer properties, but they lack specificity for their intracellular targets, leading to undesirable side effects. Herein we present a systematic study on structure-activity relationships of eight arylbenzazole-based Iridium(III) complexes of type [IrCl(Cp*)], that have revealed the role of each atom of the ancillary ligand in the physical chemistry properties, cytotoxicity and mechanism of biological action. Neutral complexes, especially those bearing phenylbenzimidazole (HL1 and HL2), restrict the binding to DNA and albumin. One of them, complex 1[C,NH-Cl], is the most selective one, does not bind DNA, targets exclusively the mitochondria, disturbs the mitochondria membrane permeability inducing proton leak and increases ROS levels, triggering the molecular machinery of regulated cell death. In mice with orthotopic lung tumors, the administration of complex 1[C,NH-Cl] reduced the tumor burden. Cancers are more vulnerable than normal tissues to a treatment that harnesses mitochondrial dysfunction. Thus, complex 1[C,NH-Cl] characterization opens the way to the development of new compounds to exploit this vulnerability.

Development of a Highly In Vivo Efficacious Dual Antitumor and Antiangiogenic Organoiridium Complex as a Potential Anti-Lung Cancer Agent

“…It is important to note here that translation of antitumor potency from in vitro cultured cells to in vivo animal models is essential for ascertaining the (pre)­clinical potential of any drug candidate but is the main hurdle in the development of new metal-based cytotoxic drugs. , Notably, IrA , IrB , and IrC (Figure ) showed tumor growth inhibition (%TGI) 57–62% as compared to respective vehicle controls in mice xenograft models. Although IrD and IrE were reported to show antitumor efficacy in vivo , % TGI was not calculated due to a lack of an appropriate vehicle control. Moreover, IrC and IrE were injected intratumorally, which is not a preferred method for the administration of chemotherapeutic agents.…”

Cellular Mechanistic Considerations on Cytotoxic Mode of Action of Phosphino Ru(II) and Ir(III) Complexes

“…In consequence, the cell cycle is disturbed and eventually, the apoptosis process is promoted. [22][23][24] Furthermore, these complexes have the ability to accumulate in intracellular lysosomes leading to their damage. The consequence of this is the aforementioned process of apoptosis.…”

“…This induces the proton leak and increases the concentration of reactive oxygen species (ROS). In consequence, the cell cycle is disturbed and eventually, the apoptosis process is promoted [22–24] . Furthermore, these complexes have the ability to accumulate in intracellular lysosomes leading to their damage.…”

Novel valproate half-sandwich rhodium and iridium conjugates to fight against multidrug-resistant Gram-positive bacteria

“…Benzimidazole core was selected for the wide range of pharmacological properties reported by this organic molecule [26][27][28] and its metal derivatives. 13,[29][30][31] Moreover, benzimidazole ligand is very versatile and can be easily derivatized to modulate the final properties of the complexes.…”

“…S34 and S35†) probably due to the exchange of the chloride ligand by the solvent. 31 Strong affinity of iridium( iii ) complexes to bind dimethyl sulfoxide is well known. 38 Then, the stability was checked in DMF- d 7 , and no changes were observed after 48 h (Fig.…”