Unveiling the anti-cancer mechanism for half-sandwich and cyclometalated Ir(iii)-based complexes with functionalized α-lipoic acid

Abstract

Alpha lipoic acid (LA) is a natural compound and coenzyme with sufficient safety information for serving as a promising anticancer agent. To further clarify the mechanism of action (MoA), two Ir(III) complexes with the functionalized α-lipoic acid (N^∧N-LA, N^∧N, 2,2-bipyridine derivative), namely Ir1 and Ir2, were synthesized, where Ir1 possessed a half-sandwich structure with the formula [Ir(Cp*)(N^∧N-LA)Cl]PF₆ (Cp* = 1,2,3,4,5-pentamethyl-cyclopentadiene) and Ir2 possessed the cyclometalated structure with the formula [Ir(C^∧N)₂(N^∧N-LA)]PF₆ (C^∧N = 2-phenylpyridine). Even though both complexes were constructed based on the same N^∧N-LA ligand, Ir1 showed no cytotoxicity (IC₅₀ > 200 μM), which was due to its low lipophilicity for hard penetration into the cancer cells, easy hydrolysis, and reaction with GSH. Ir2 exhibited excellent cytotoxicity (IC₅₀ = 3.43–6.74 μM) toward diverse cancer cell lines in vitro and a promising ability to overcome the cisplatin-resistance in A549R cells. The anticancer mechanism of Ir2 in A549 cells was investigated in detail, and it was found it could localize and accumulate in the lysosomes of A549 cells, induce ROS, arrest the cycle at G₀/G₁, and lead to cell death by autophagy. Comparison with Ir-NH₂ ([Ir(C^∧N)₂(N^∧N-NH₂)]PF₆) demonstrated that introduction of the LA ligand to Ir2 could highly enhance the cytotoxicity and help to overcome the cisplatin-resistance. This study of the half-sandwich and cyclometalated Ir(III)-based anticancer agents highlighted the different MoAs toward cancer cells and provided new insights for understanding their structure–property relationships.