Mitochondria-localizing dicarbohydrazide Ln complexes and their mechanism of in vitro anticancer activity

Abstract

In this study, two novel organic ligands, bis(salicylaldehyde)pyrazino-1,10-phenanthroline-7,10-dicarbohydrazide (L) and bis(salicylaldehyde)-1,10-phenanthroline-7,10-dicarbohydrazide (L¹), were synthesized. These ligands were used to react with lanthanide(III) acetate to obtain complexes 1–6, namely, [Dy₅(L)₂(CH₃COO)₅(CH₃OH)(μ₃-OH)(μ₂-OH)(H₂O)]·2CH₃OH (1), [Tb₅(L)₂(CH₃COO)₅(CH₃OH)(μ₃-OH)(μ₂-OH)(H₂O)]·3CH₃OH (2), [Gd₅(L)₂(CH₃COO)₅(CH₃OH)(μ₃-OH)(μ₂-OH)(H₂O)]·3CH₃OH (3), [Dy₅(L¹)₂(μ₂-OH)(μ₃-OH)(CH₃COO)₅(CH₃OH)(H₂O)₂]·2H₂O (4), [Dy₅(L¹)₂(μ₃-OH)(CH₃COO)₆(CH₃OH)₃]·CH₃OH (5), and [Dy₅(L¹)₂(μ₂-OH)₂(μ₃-OH)(CH₃COO)₄(CH₃OH)(H₂O)₂]·CH₃OH (6). Fluorescence studies demonstrated that complexes 1–6 show appreciable fluorescence in the yellow-green region. In vitro antitumor screening revealed that complex 1 exhibits better inhibitory activities than the commercial anticancer drug cisplatin against SK-OV-3 and A549 tumor cell lines, with IC₅₀ values of 8.09 ± 1.25 and 13.26 ± 0.39 μM, respectively. All six complexes showed low cytotoxicity toward normal human liver HL-7702 cells compared with cisplatin. Complexes 1 and 3 induced the highest apoptosis rate of SK-OV-3/DDP cells. They also bind to DNA via an intercalative mode with the binding constant K_q values of 1.6 × 10⁴ and 1.19 × 10⁴ L mol⁻¹, respectively. Confocal fluorescence imaging ascertained that complexes 1 and 3 are primarily localized in the mitochondria. Further studies revealed that these complexes trigger SK-OV-3/DDP cell apoptosis via a mitochondrial dysfunction pathway, which is probably caused by the reduction of the mitochondrial membrane potential and the induction of reactive oxygen species production.