Theoretical and experimental investigation of anticancer activities of an acyclic and symmetrical compartmental Schiff base ligand and its Co(ii), Cu(ii) and Zn(ii) complexes

Abstract

A compartmental Schiff base ligand, 2,2'-((((((2-hydroxypropane-1,3-diyl)bis(oxy))bis(2,1-phenylene))bis(methylene))bis(azanylylidene))bis(methanylylidene))bis(4-bromophenol) (H₃L^Br) and its complexes with cobalt(ii), copper(ii) and zinc(ii) including, [Co(HL^Br)] (1), [Cu₂(L^Br)(μ-1,3-OAc)]·MeOH (2) and [Zn(HL^Br)] (3) were prepared using template synthesis and characterised by elemental analysis, FT-IR and ¹H NMR spectroscopies and single-crystal X-ray diffraction. In the structure of complexes 1 and 3 the metal atom has a MN₂O₂ environment with tetrahedral geometry while complex 2 has a binuclear structure with a MNO₄ environment and square planar geometry around the copper atom. The ability of all compounds to interact with the nine biomacromolecules (BRAF kinase, CatB, DNA gyrase, HDAC7, rHA, RNR, TrxR, TS and Top II) are investigated by docking calculations. For examination of the docking results, the in vitro activities of eight compounds against the human leukemia cell line K562 was investigated by evaluation of IC₅₀ values and mode of cell death (apoptosis).

Scheme 1. Structure of the two synthesized ligands (H₃L^NO2, H₃L^Br).

Fig. 1. ORTEP diagram of the molecular structure of 1. The ellipsoids are drawn at the 20% probability level. The hydrogen atoms were deleted for clarity.

Fig. 2. Packing of 1, showing the π–π stacking interactions. Each CoN₂O₂ unit is shown as tetrahedron.

Scheme 2. Coordinated bond lengths average for all cobalt (a) and zinc (b) complexes containing the presented moiety.

Fig. 3. Pie chart, the percentage of different geometries around the cobalt atom among the analogues of the complex 1. Geometry for τ_sq values lower than the 0.5 is tetrahedron and higher than the 0.5 is square plane.

Fig. 4. ORTEP diagram of the molecular structure of 2. The ellipsoids are drawn at the 20% probability level.

Fig. 5. Pie chart, the percentage of different coordination modes of the acetato ligand among the complexes of the copper.

Fig. 6. ORTEP diagram of the molecular structure of 3. The ellipsoids are drawn at the 20% probability level. The hydrogen atoms were deleted for clarity.

Fig. 7. Packing of 3, showing the π–π stacking and hydrogen bonds. Each ZnN₂O₂ unit is shown as tetrahedron.

Fig. 8. Pie chart, the percentage of different geometries around the zinc atom among the analogues of the complex 3. Geometry for τ values lower than the 0.5 is square pyramid and higher than the 0.5 is trigonal bi pyramid.

Fig. 9. Variation diagram of total intermolecular interactions energy (E) for complexes 1–3 with increasing the number of surrounding molecules.

Fig. 10. Optimized structure of the H₃L^Br ligand.

Fig. 11. Docking study results, showing the interaction between H₃L^Br and BRAF kinase protein.

Fig. 12. Docking study results, showing the interaction between complex 1 and BRAF kinase protein.