Anticancer activities of a β-amino alcohol ligand and nanoparticles of its copper(ii) and zinc(ii) complexes evaluated by experimental and theoretical methods

Abstract

2-(2-(2-Hydroxyethylamino)ethylamino)cyclohexanol (HEAC) and copper and zinc complexes, [Cu(HEAC)Cl]Cl (1), [Cu(HEAC)Br]Br (2), [Zn(HEAC)Cl₂] (3), were prepared and identified by elemental analysis, FT-IR, UV-Vis, ¹H NMR spectroscopy and single-crystal X-ray diffraction. Also nanoparticles of 1-3 were prepared for anticancer studies by ultrasonic irradiation. Particle size and morphology of the nano particles are investigated by PXRD and SEM, respectively. X-ray analysis revealed that the ionic complexes 1 and 2 are isostructural. In the structure of complexes 1 and 2, the metal atom has a CuN₂O₂X (X: Cl (1), Br (2)) environment with square-pyramidal geometry, containing the tetradentate N₂O₂-donor HEAC. The bond length of the axial position in the square-pyramidal geometry of 1 and 2 is elongated. Complex 3 has a ZnN₂OCl₂ environment with trigonal bipyramidal geometry around the zinc atom in which the HEAC acts as mer-N₂O-donor. The ability of HEAC and nano particles 1-3 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 four compounds against the human leukemia cell line K562 were investigated by evaluation of IC₅₀ values and mode of cell death (apoptosis). The thermodynamic stability of the compounds along with the charge distribution pattern were studied by DFT and NBO analysis, respectively.

Scheme 1. The structure of the 2-(2-(2-hydroxyethylamino)ethylamino)cyclohexanol (HEAC).

Fig. 1. The ortep diagram of the molecular structure of the complex 1. The ellipsoids are drawn at the 50% probability level.

Fig. 2. Packing of the complex 1, showing the hydrogen bonds. Only the hydrogen atoms involved in hydrogen bonding are shown. Each CuN₂O₂Cl unit is shown as square-pyramid. Also R⁶₄(20) hydrogen bond motifs between four complexes 1 is shown.

Scheme 2. Different types of the analogues of the complex 1.

Fig. 3. Percentage of square-pyramidal and trigonal bi pyramidal geometries around the copper atom among the analogues of the complex 1.

Fig. 4. Column chart of the percentage of different geometries around the penta-coordinated copper (blue columns) and zinc (orange columns) atoms in the CSD database.

Fig. 5. The ortep diagram of the molecular structure of the complex 2. The ellipsoids are drawn at the 50% probability level.

Fig. 6. The ortep diagram of the molecular structure of the complex 3. The ellipsoids are drawn at the 50% probability level.

Fig. 7. Packing of the complex 3, showing the hydrogen bonds. Only the hydrogen atoms involved in hydrogen bonding are shown. Each ZnN₂OCl₂ unit is shown as trigonal bi pyramid. Also R⁶₄(20) hydrogen bond motifs between six complexes 3 is shown.

Fig. 8. Variation diagram of total intermolecular interactions energy (E) for complexes 1 and 2 with increasing the number of surrounding molecules.

Fig. 9. PXRD pattern (middle) and SEM images (upper) of the nano complex 1. Also single crystal X-ray diffraction pattern of 1 (under) is presented.

Fig. 10. PXRD pattern (middle) and SEM images (upper) of the nano complex 2. Also single crystal X-ray diffraction pattern of 2 (under) is presented.

Fig. 11. PXRD pattern (middle) and SEM images (upper) of the nano complex 3. Also single crystal X-ray diffraction pattern of 3 (under) is presented.

Fig. 12. Docking study results, showing the interaction between HEAC ligand and BRAF kinase protein.

Fig. 13. Docking study results, showing the interaction between the complex 1 and BRAF kinase protein.