Chirality-controlled biomolecular recognition in Cu(I) metallodrugs: the first enantiomorphic CuP2O2 systems with dual DNA/LOX activity

Abstract

Copper(II) nitrate reacts with tris(m-tolyl)phosphine (m-MePh)3P) in 1:2 and 1:3 molar ratios to form [Cu((m-MePh)3P)2(NO3)] (1) which contains two isomers (1A) and (1B) in the crystal lattice and [Cu((m-MePh)3P)3(NO3)] (2). The reaction of copper(II) nitrate with tris(p-tolyl)phosphine (p-MePh)3P in 1:3 molar ratio results in the {[Cu((p-MePh)3P)3(NO3)]·(DMF)·(H2O)} (3) complex. The complexes were characterized in solid state by melting point (m.p), X-ray fluorescence spectroscopy (XRF), attenuated total reflectance-Fourier transform infra-red (ATR-FT-IR), and in solution by cryoscopy, Ultraviolet-Visible (UV-Vis) and Nuclear Magnetic Resonance (1H-NMR) spectroscopies. Their crystal structures were determined by single crystal X-ray crystallography in solid state while the molecular weight was calculated by cryoscopy. A CCDC search shows that 1A and 1B are the first known chiral Cu(I) complexes of CuP2O2 core. Binding affinity of complexes 1-3 toward calf thymus DNA (CT-DNA) was investigated ex vivo using UV-Vis and fluorescence spectroscopies, viscosity measurements, and DNA denaturation assays. Their lipoxygenase (LOX) inhibitory activity is also studied. In silico computations further rationalized the DNA and LOX interactions with 1-3. In vitro assays were conducted to evaluate the activity of 1-3 against human breast adenocarcinoma (MCF-7) cells, and the results are presented herein.