New Organometallic Tetraphenylethylene⋅Iridium(III) Complexes with Antineoplastic Activity

Abstract

Iridium(III) complexes have attracted more and more attention in the past few years because of their potential antineoplastic activity. In this study, four Ir^III complexes of the types [(η⁵ -Cp^x )Ir(N^N)Cl]PF₆ (complexes 1 and 2) and [Ir(Phpy)₂ (N^N)]PF₆ (complexes 3 and 4) have been synthesized and characterized. They exhibit potential antineoplastic activity towards A549 cells, especially in the case of complex 1 [IC₅₀ =(3.56±0.5) μm], which was nearly six times as effective as cisplatin [(21.31±1.7) μm]. Additionally, these complexes show some selectivity towards cancer cells over normal cells. They could be transported by serum albumin (binding constants were changed from 0.37×10⁵ to 81.71×10⁵ m^-1 ). Ir^III complexes 1 and 2 could catalyze the transformation of nicotinamide adenine dinucleotide reduced form (NADH) into NAD⁺ (turnover numbers 43.2, 11.9] and induce the accumulation of reactive oxygen species, thus confirming their antineoplastic mechanism of oxidation, whereas the cyclometalated complexes 3 and 4 were able to target the lysosome [Pearson co-localization coefficient (PCC)=0.73], cause lysosomal damage, and induce apoptosis. Understanding the mechanism of action would help further structure-activity optimization on these Ir^III complexes as emerging cancer therapeutics.

Keywords: antitumor agents; iridium complexes; organometallic chemistry; structure-activity relationships; tetraphenylethylene.