Mechanochemical synthesis and antiproliferative activity of novel ferrocene quinoline/quinolone hybrids

Abstract

The synthesis of novel 1,1′‐disubstituted ferrocene conjugates appended with N‐1 and O‐4 alkylated quinolone and quinoline was reported. The target compounds were synthesized employing a liquid‐assisted grinding (LAG) mechanochemical method in copper‐catalyzed azide‐alkyne cycloaddition (CuAAC) to obtain ferrocene−quinoline/quinolone hybrids (5a–5d, 6a–6d, 7a, 7b, 8a, and 8b) in higher yields and shorter reaction time compared to a conventional method, thus proving superiority of mechanochemistry versus conventional synthesis. Bis‐quinoline and bis‐quinolone ferrocene derivatives were evaluated for their antiproliferative effects on five selected tumor and two non‐tumor cell lines. Bis‐6‐methylquinolone–ferrocene conjugate 8b showed the best antiproliferative effect on T‐cell lymphoma (HuT78) cells (IC50 = 14.8 μM) and no cytotoxicity on both non‐tumor MDCK1 and BJ cells. Results obtained after mitochondrial membrane potential (∆Ψm) measurement using flow cytometry showed that compound 8b caused accumulation of HuT78 cells in subG0/G1 phase, disturbance of mitochondrial membrane potential, and apoptosis. The structure of the quinolone and ferrocene hybrid 8b can be further optimized to obtain candidates with better inhibitory effects on HuT78 cells.