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 the solid state using melting point (m.p), X-ray fluorescence spectroscopy (XRF), and attenuated total reflectance-Fourier transform infra-red (ATR-FT-IR) spectroscopy, and in solution using cryoscopy, ultraviolet–visible (UV-vis) and nuclear magnetic resonance (¹H-NMR) spectroscopy. Their crystal structures were determined using single crystal X-ray crystallography in the solid state while the molecular weight was calculated using cryoscopy. A CCDC search shows that 1A and 1B are the first known chiral Cu(I) complexes of the CuP₂O₂ core. Binding affinity of complexes 1–3 toward calf thymus DNA (CT-DNA) was investigated ex vivo using UV-vis and fluorescence spectroscopy, viscosity measurements, and DNA denaturation assays. Their lipoxygenase (LOX) inhibitory activity was 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.