Selective cytotoxicity of [Cu(theophylline)(H2O)2Cl2] complex toward cancer cells: insights from structural, spectroscopic, and molecular docking analyses.

The diaquadichlorotheophylline-copper(ii) coordination complex, [Cu(theophylline)(H2O)2Cl2], was synthesized via slow solvent evaporation and comprehensively characterized through experimental and computational approaches. X-ray powder diffraction and Rietveld refinement confirmed a triclinic crystal system (space group P1̄(C 1 i )) with pentacoordinate copper(ii) in a square-pyramidal geometry. Thermal analyses revealed thermal stability up to 358 K, with dehydration requiring 89.5 kJ mol-1 per H2O molecule. Vibrational spectroscopy (Fourier transform infrared and Raman) combined with density functional theory calculations (PBE1PBE/6-311++G(d,p)) provided suitable mode assignments and demonstrated excellent agreement between experimental and calculated spectra, including solvent effects using the IEFPCM model. Frontier molecular orbital analysis yielded the highest occupied molecular orbital-lowest unoccupied molecular orbital gaps of approximately 3.8 eV and electrophilicity indices of approximately 6.8 eV, indicating good chemical stability and biological potential. Ultraviolet-visible-near infrared spectroscopy revealed characteristic d-d transitions for pentacoordinate copper(ii) and π → π*/n → π* transitions from the theophylline ligand. Molecular docking predicted a strong in silico binding affinity to deoxyribonucleic acid (K i = 5.85 µM, binding free energy = -7.14 kcal mol-1), consistent with an intercalative mode and moderate affinity to bovine serum albumin (K i = 40.78 µM, binding free energy = -5.99 kcal mol-1). Cytotoxicity assays against PC-3 (prostate), MDA-MB-231 (breast), and HCT-116 (colorectal) cancer cell lines revealed dose-dependent activity with half-maximal inhibitory concentration values ranging from 2.91 to 3.77 µM and selectivity indices greater than 1 compared to the non-tumorigenic GM07429A cell line, with preferential activity against breast cancer. These results indicate that diaquadichlorotheophylline-copper(ii) is a promising anticancer candidate with favorable selectivity for malignant cells over healthy tissue, warranting further preclinical evaluation.