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.
Highlights
The endogenous disul de a-lipoic acid (LA) is accepted as a promising anticancer agent due to its potent activities toward various cancer cell lines at concentrations in the mM range.[1,2] Most importantly, LA is a natural compound and coenzyme with sufficient safety information,[3,4] which facilitates its use in cancer patients to support chemotherapy
Syntheses and characterization Complexes Ir1 and Ir2 were synthesized from the functionalized a-lipoic acid ligand (N^N-LA) with distinct dinuclear precursors [(h5-Cp*)IrCl2]2 and [Ir(ppy)2Cl]2, respectively (Scheme S1†)
Compared to the traditional cisplatin reacting with DNA in the nucleus and leading to cell death through apoptosis, most Ir(III)-based cancer agents, as previously reported, underwent the apoptosis death path;[25] whereas cyclometalated Ir2 could localize and accumulate in the lysosomal organelle of A549 cancer cells and induce partial necrosis and autophagic cell death, which is distinct from the apoptosis induced by LA itself. These results demonstrated that Ir2 with the functionalized N^N-LA ligand could be utilized in cancer treatment due to its promising anticancer activity
Summary
The endogenous disul de a-lipoic acid (LA) is accepted as a promising anticancer agent due to its potent activities toward various cancer cell lines at concentrations in the mM range.[1,2] Most importantly, LA is a natural compound and coenzyme with sufficient safety information,[3,4] which facilitates its use in cancer patients to support chemotherapy. Metal-based anticancer agents have exhibited excellent efficiency in clinical treatment toward various types of carcinomas over the past several decades.[8,9] several physiological limits and clinical issues have arisen with cisplatin and its derivatives, such as poor selectivity, serious toxic side effects, strong drug resistance, and low biological utilities.[10,11] there is an urgent need to develop new generations of metal anticancer agents in the eld of metallodrugs.[12,13,14,15] Recently, the third-row transition metal iridium (Ir) has attracted much attention due to its variety of oxidation states, coordination numbers, coordination geometries, and catalytic properties.[16,17] Sadler and Liu et al established a clear relationship between cyclopentadienyl ligands and the anticancer activity of half-sandwich Ir(III) complexes.[18,19] Chao et al achieved the organelle-targeting of cyclometalated Ir(III) complexes by regulating the relevant ligands to adjust their lipophilicity.[20]
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