Solvent-driven structural topology involving energetically significant intra- and intermolecular chelate ring contacts and anticancer activities of Cu(ii) phenanthroline complexes involving benzoates: experimental and theoretical studies

Abstract

Two new coordination solids [Cu₂(μ²-Bz)₄(CH₃OH)₂][Cu₂(η²-Bz)₂(phen)₂(H₂O)₂]·(NO₃)₂ (1) and [Cu(phen)(H₂O)(Bz)(η²-Bz)] (2) (phen = 1,10-phenanthroline; Bz = benzoate) have been synthesized and characterized using elemental analysis, TGA, spectroscopic (IR, UV-vis-NIR and ESR) and single crystal X-ray diffraction techniques. Change of the solvent from methanol to DMF results in changes in the architectures that are triggered by a change from square pyramidal to octahedral coordination at the divalent metal centers for complexes 1 and 2 respectively. The structural topology of the complexes is established by the interplay of strong O-H⋯O and weak C-H⋯O, C-H⋯C, π-π stacking interactions. Unconventional parallel intramolecular and anti-parallel intermolecular contacts involving the chelate rings (CR) also stabilize the structures. The energetic analyses of the structures evidence that the parallel arrangement is energetically favoured which is likely due to the presence of the Cu⋯Cu cuprophilic interaction in 1 that is not established in 2. Compound 1 exhibits the highest antibacterial activity against Rhizobium leguminosarum among the tested cultures. In vitro cytotoxicity and apoptosis studies were carried out for compounds 1 and 2 on malignant Dalton's lymphoma cell line (DL). Both compounds showed a significant effect on the decrease in cell viability as compared to a control, while compound 2 induced remarkable cytotoxicity towards DL cells. Treatment also showed the appearance of membrane blebbing, chromatin condensation and fragmented nuclei which are typical characteristic features of apoptotic cell death. Furthermore, a docking study revealed that both compounds docked in the active sites of all the cancer target proteins under study. Moreover, SAR analysis revealed that oxygen and nitrogen atoms of compound 1 and the oxygen atoms of compound 2 are crucial for biological activities.

Scheme 1. Synthesis of compound 1 and 2.

Fig. 1. Molecular structure of 1.

Fig. 2. Molecular structure of 2.

Fig. 3. (a) Intramolecular interactions in cationic unit of compound 1. (b) Formation of supramolecular dimer of complex moieties of 1.

Fig. 4. Weak interaction present between the molecules present in asymmetric unit of 1.

Fig. 5. 2D layered architecture of compound 1.

Fig. 6. (a) Significant C–H⋯C contacts observed between two monomeric units of 2. (b) Propagation of 1D chain of cationic moieties of 2.

Fig. 7. Layered architecture of compound 2 along the ab plane.

Fig. 8. (a) Partial view of the X-ray structure of compound 1. (b) Conformation of complex 1 without the π-stacking interaction. (c) NCI surface of compound 1. The gradient cut-off is s = 0.35 au, and the color scale is −0.04 < ρ < 0.04 au.

Fig. 9. (a) Dimer retrieved from the crystal structure of compound 2 (distances in Å). (b) Model without the benzoate moiety, which has been replaced by H-atoms. (c) NCI surface of the dimer of compound 2. The gradient cut-off is s = 0.35 au, and the color scale is −0.04 < ρ < 0.04 au.

Fig. 10. (a and b) ESR spectra of crystalline solid of complexes 1 and 2.

Fig. 11. Thermogravimetric analyses of compound 1 and 2.

Fig. 12. Petri plate showing the zone of inhibition of compound 1 with concentration 150 μg mL⁻¹.

Fig. 13. Comparison of the antibacterial activities of the complexes and phenanthroline.

Fig. 14. Upper panel showed cell viability results after compound 1, compound 2 and cisplatin treatment. A peripheral blood mononuclear cell (PBMC) was used as normal cells. Compound 2 significantly decreases cell viability as compared to compound 1. Lower panel showed IC₅₀ values for compound 1, compound 2 and cis-platin after 24 hours treatment. Data are mean ± S.D., n = 3, ANOVA, P ≤ 0.05.

Fig. 15. Upper panel showed morphological features of apoptotic and viable cells with acridine orange and ethidium bromide (AO/EB) staining. Control DL cells showed mostly viable cells, cisplatin, complexes 1 and 2 treated group showing apoptotic features evident by red/orange nuclei with membrane damage and blebbing. Scale bar 10 μm. Lower panel showed percentage apoptotic cells after treatment with complexes 1, 2 and the reference drug, cis-platin. Data are mean ± S.D., n = 3, ANOVA, P ≤ 0.05.

Fig. 16. Docking structure of compound 1 with B-RAF kinase (a), EGFR kinase domain (b) and CC chemokine receptor (c), no interaction was observed for PI3K-gamma receptors. (a), (b) and (c): docking with cationic part of 1 and (a′), (b′) and (c′): docking with neutral part of 1. Different types of chemical interactions are shown in dotted lines with respective nomenclature.

Fig. 17. Docking structure of compound 2 with B-RAF kinase (a) PI3K-gamma receptors (b), CC chemokine receptor (c) and EGFR kinase domain (d) different types of chemical interactions are shown in dotted lines with respective nomenclature.

Fig. 18. Docking scores of compounds 1 and 2 with B-RAF kinase, CC chemokine receptor, EGFR kinase domain and PI3K-gamma receptors. The reference inhibitors for B-RAF kinase, CC chemokine receptor, EGFR kinase domain and PI3K-gamma receptors are dabrafenib, vercirnon, quinazoline and AMG-511 respectively. As per MVD docking score parameters lowest the score better is the interactions. Data are mean ± SD, n = 3, ANOVA, P ≤ 0.05.

Fig. 19. (a and b) Structure Activity Relationships (SAR) of cationic part of compound 1 and compound 2.