Azide-mediated unusual in situ transformation of Mannich base to Schiff–Mannich base and isolation of their Cu(ii) complexes: crystal structure, theoretical inspection and anticancer activities

Abstract

A new “end-off” compartmental Mannich ligand (HL¹) namely 3-((bis(2-methoxyethyl)amino)methyl)-5-bromo-2-hydroxybenzaldehyde containing two methoxyethyl pendant arms and one-CHO functionality has been synthesized through conventional C–C and C–N coupling reactions. On treatment with Cu(ClO₄)₂, HL¹ yields a dinuclear μ-phenolatocopper(II) complex having the molecular formula [Cu₂(L¹)₂](ClO₄)₂(H₂O)_1.5 (1). Surprisingly, the ligand HL¹ is radically transformed into a new asymmetric Schiff–Mannich base ligand (HL^F) in the presence of NaN₃ and Cu(ClO₄)₂ forming a unique dinuclear centro-symmetric Cu(II) complex [Cu(L^F)]₂ (2) as evident from single-crystal X-ray diffraction (SCXRD) analysis. A probable mechanistic rationalization has been proposed on the basis of theoretical calculations, which suggests systematic fragmentation of HL¹ in the presence of azide residue and re-condensation of the fragmented units to yield the final Cu-HL^F complex (2). SCXRD analysis portrays a large inter-metallic distance in complex 2 in comparison with complex 1 (5.493 vs. 2.989 Å, respectively) along with other distinct structural features. After physicochemical characterization both the complexes have been exploited to evaluate their possible anticancer proficiency on lung adenocarcinoma cell line (A549). Complex 1 distinctly impeded the proliferation of lung adenocarcinoma cells in a dose-dependent manner more efficiently than complex 2. Due to the behavior of complex 1 as potential therapeutics, cellular transformations of A549 cells have been systematically investigated. As evidenced from various in vitro experiments, the cell death mechanism triggered by complex 1 turned out to be apoptosis, as indicated by the DNA fragmentation, chromatin condensation, membrane blebbing and imbalanced cell cycle distribution as well as retard migration in A549 cells.