Unravelling the mechanism of apoptosis induced by copper(ii) complexes of NN2-pincer ligands in lung cancer cells

Abstract

The invention of efficient chemotherapeutic drugs is essential for human health and development. Keeping this in mind, a series of copper(II) pincer complexes, 1–4, of ligands L1(H) = 2-morpholino-N-(quinolin-8-yl)acetamide, L2(H) = 2-di-n-propylamino-N-(quinolin-8-yl)acetamide, L3(H) = 2-di-n-butylamino-N-(quinolin-8-yl)acetamide and L4(H) = 2-di-n-benzylamino-N-(quinolin-8-yl)acetamide have been synthesized, characterized, and utilized for inhibiting cancer proliferation. Complexes 1–4 showed very efficient activity against lung (A549) and breast (MCF-7) cancer cells, which are the most frequently diagnosed cancers according to the WHO. Among them, 1 was highly active against lung cancer cells with an IC₅₀ value of 8 μM, showing no toxicity towards common L929 fibroblast cell lines (IC₅₀ > 1000 μM). Moreover, AO–EB staining inferred that this cellular demise was attributed to apoptosis, which was determined to be 25.91% of cells by flow cytometry at the IC₅₀ concentration. Furthermore, carboxy-H₂DCFDA staining revealed the involvement of ROS in the mechanism. Interestingly, JC-1 dye staining revealed a change in the potential of the mitochondrial membrane, which indicates the enhanced production of ROS in mitochondria. A deep search for the mechanism through in silico studies guided us to the fact that complexes 1–4 might perturb the function of complex I in mitochondria. Furthermore, the studies can be expanded towards clinical applications mainly with morpholine appended complex 1.