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Abstract
A series of cobalt(III) salophen-type Schiff base complexes bearing methoxy substituents at the 3-, 4-, and 5-positions of the ligand, along with linear-chain alkyl amines of varying lengths (heptylamine vs. dodecylamine), were synthesized and characterized. DNA binding constants (Kb) ranged from 2.290 × 104 M⁻¹ (complex 1) to 4.628 × 104 M⁻¹ (complex 6), as determined by viscosity and ethidium bromide displacement studies, supporting a mixed groove–intercalative binding mode. Bovine serum albumin (BSA) fluorescence quenching experiments yielded binding constants up to 5.102 × 106 M⁻¹ (complex 5), with positive entropy changes indicating a significant hydrophobic contribution. DFT calculations were performed to probe the electronic structures of these metal complexes. Molecular docking analyses revealed stabilizing interactions of the 5-methoxy substituent with nucleobases and preferential positioning near Trp-212 in BSA. In A549 lung carcinoma cells, the 5-methoxy dodecylamine complex (complex 6) exhibited the highest cytotoxicity (IC50 = 32 μM), surpassing the unsubstituted analogue (65 μM) and comparable to cisplatin (30 μM) under identical conditions. Importantly, cell-cycle analysis revealed a structure-dependent bifurcation: complexes 1, 3, and 5 predominantly induced Sub-G₀/G₁ populations, whereas complexes 2, 4, and 6 promoted G₂/M arrest. These findings establish a coherent structure–activity relationship (SAR) in which methoxy position and axial-ligand hydrophobicity govern biomolecular interactions and translate into distinct cellular outcomes, providing design principles for future cobalt(III) complex-based anticancer agents.
Supplementary materials
Title
Supporting Information for Methoxy Substitution and Alkyl Ligand Chain-Length Effects on DNA/BSA Binding and Anticancer Activity of Cobalt(III) Schiff Base Complexes
Description
This Supporting Information includes detailed experimental and computational data for the cobalt(III) Schiff base complexes studied in the main article. It contains:
FT-IR spectra (Fig. S1) and NMR spectra (Figs. S2–S7) for complexes 1–6.
ESI-MS spectra (Figs. S8–S10) confirming the molecular masses of the complexes.
DNA binding studies, including absorption spectra (Fig. S11), emission spectra with EB (Fig. S12), and viscosity measurements (Fig. S13).
BSA interaction studies, including fluorescence quenching (Figs. S14–S16).
Computational studies: optimized geometries, frontier molecular orbitals, and electrostatic potential maps (Figs. S17–S19).
Molecular docking studies with B-DNA and BSA (Figs. S20–S21).
Cytotoxicity and apoptosis/necrosis analysis in A549 lung cancer cells (Figs. S22–S23).
Selected bond parameters from DFT calculations (Table S1) and molecular docking details (Table S2).
This information supports and complements the experimental and theoretical analyses described in the main article.
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