Discovery of thirteen cobalt(ii) and copper(ii) salicylaldehyde Schiff base complexes that induce apoptosis and autophagy in human lung adenocarcinoma A549/DDP cells and that can overcome cisplatin resistance in vitro and in vivo

Abstract

In this study, 13 transition metal complexes, namely, [Cu(L¹H)(H₂O)₂]·(H₂O)·NO₃ (1), [Cu(LⁿH₂)₂]·(NO₃)·(H₂O)₂ (2, n = 2; 3, n = 3; 4, n = 4; 5, n = 5), [Co(LⁿH)₂]₂·(H₂O)_0.5 (6, n = 2; 7, n = 3; 8, n = 4; 9, n = 5), [Cu(L⁶H)_0.5(L¹⁰H)_0.5(phen)]·(CH₃OH)_0.25 (10), [Cu(L¹¹H) (phen)]₄·(H₂O)₉ (11), [Cu(L⁸H)_0.27(L¹²H)_0.73(phen)]₄·(H₂O)_5.5(CH₃OH) (12), and [Cu(L⁹H) (phen)]₃·(H₂O)₇·(CH₃OH) (13), were synthesized using Schiff base ligands and characterized by elemental analysis (EA), infrared spectroscopy (IR), and single-crystal X-ray diffraction (SC-XRD). Compared with complexes 1–9, complexes 10–13 displayed stronger cytotoxic activities against the tested A549/DDP cancer cells (IC₅₀ = 0.97–3.31 μM), with differences greater than one order of magnitude. Moreover, complexes 11 and 13 could induce apoptosis and autophagy in A549/DDP cells via the mitochondrial dysfunction pathway that affects the regulation of autophagy- and mitochondrial-related proteins. Importantly, the results indicate that the two novel salicylaldehyde Schiff base analogs, 11 and 13, exhibited pronounced and selective activity against A549/DDP xenografts in vivo.