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
