Density Functional Theory-Guided Photo-Triggered Anticancer Activity of Curcumin-Based Zinc(II) Complexes

Photodynamic therapy (PDT) has evolved as a new therapeutic modality for cancer treatment with fewer side effects and drug resistance. Curcumin exhibits PDT activity, but its low bioavailability restricts its clinical application. Here, the bioavailability of curcumin was increased by its complex formation with the Zn(II) center. For a structure-activity relationship study, Zn(II)-based complexes ( - ) comprising N^N-based ligands (2,2'-bipyridine in and or 1,10-phenanthroline in ) and O^O-based ligands (acetylacetone in , monoanionic curcumin in and ) were synthesized and thoroughly characterized. The X-ray structure of the control complex, , indicated a square pyramidal shape of the molecules. Photophysical and TD-DFT studies indicated the potential of and as good visible light type-II photosensitizers for PDT. Guided by the TD-DFT studies, the low-energy visible light-triggered singlet oxygen ( O ) generation efficacy of and was explored in solution and in cancer cells. As predicted by the TD-DFT calculations, these complexes produced O efficiently in the cytosol of MCF-7 cancer cells and ultimately displayed excellent apoptotic anticancer activity in the presence of light. Moreover, the molecular docking investigation showed that complexes and have very good binding affinities with caspase-9 and p-53 proteins and could activate them for cellular apoptosis. Further molecular dynamics simulations confirmed the stability of in the caspase-9 protein binding site.