RESUMO
The spatiotemporal control over the drug's action offered by ruthenium(II) polypyridyl complexes by the selective activation of the prodrug inside the tumor has beaconed toward much-desired selectivity issues in cancer chemotherapy. The photocaging of anticancer bioactive ligands attached synergistically with cytotoxic Ru(II) polypyridyl cores and selective release thereof in cancer cells are a promising modality for more effective drug action. Diallyl sulfide (DAS) naturally found in garlic has anticancer, antioxidant, and anti-inflammatory activities. Herein, we designed two Ru(II) polypyridyl complexes to cage DAS having a thioether-based donor site. For in-depth photocaging studies, we compared the reactivity of the DAS-caged compounds with the uncaged Ru(II)-complexes with the general formula [Ru(ttp)(NN)(L)]+/2+. Here, in the first series, ttp = p-tolyl terpyridine, NN = phen (1,10-phenanthroline), and L = Cl- (1-Cl) and H2O (1-H2O), while for the second series, NN = dpq (pyrazino[2,3-f][1,10]phenanthroline), and L = Cl- (2-Cl) and H2O (2-H2O). The reaction of DAS with 1-H2O and 2-H2O yielded the caged complexes [Ru(ttp)(NN)(DAS)](PF6)2, i.e., 1-DAS and 2-DAS, respectively. The complexes were structurally characterized by X-ray crystallography, and the solution-state characterization was done by 1H NMR and ESI-MS studies. Photoinduced release of DAS from the Ru(II) core was monitored by 1H NMR and UV-vis spectroscopy. When irradiated with a 470 nm blue LED in DMSO, the photosubstitution quantum yields (Φ) of 0.035 and 0.057 were observed for 1-DAS and 2-DAS, respectively. Intriguing solution-state speciation and kinetic behaviors of the uncaged and caged Ru(II)-complexes emerged from 1H NMR studies in the dark, and they are depicted in this work. The caged 1-DAS and 2-DAS complexes remained mostly structurally intact for a reasonably long period in DMSO. The uncaged 1-Cl and 2-Cl complexes, although did not undergo substitution in only DMSO but in the 10% DMSO/H2O mixture, completely converted to the corresponding DMSO-adduct within 16 h. Toward gaining insights into the reactivity with the biological targets, we observed that 1-Cl upon hydrolysis formed an adduct with 5'-GMP, while a small amount of GSSG-adduct was observed when 1-Cl was reacted with GSH in H2O at 323 K. 1-Cl after hydrolysis reacted with l-methionine, although the rate was slightly slower compared with that with DMSO, suggesting varying reaction kinetics with different sulfur-based linkages. Although 1-H2O reacted with sulfoxide and thioether ligands at room temperature, the rate was much faster at higher temperatures obviously, and thiol-based systems needed higher thermal energy for conjugation. Overall, these studies provide insight for thoughtful design of new generation Ru(II) polypyridyl complexes for caging suitable bioactive organic molecules.
