Ligand Modifications on a Cp(quinolate)Ru Catalyst to Improve Its Stability in a Bio-orthogonal Deprotection Reaction

The deprotection or activation of substances in biological systems is of particular interest as this method can be used to activate prodrugs in a site- and time-specific manner, thus minimizing possible side effects. Investigations of the literature-known Ru catalyst [RuCp(QL)(η3-allyl)PF6] (with Cp = η-cyclopentadienide, QL= 5-(methoxycarboyl)-8-quinolinolate, 5c) revealed stability issues of the dissolved catalyst in air. We surmised that a more stable catalyst would perform better under biologically relevant conditions and that classical modifications in the ligand set would affect such improved properties. In this work, a systematic study is reported to modify the Cp ligand by using Cp* (Cp* = η-pentamethyl-cyclopentadienide), trimethylsilyl Cp, or t-butyl Cp instead and on the allyl ligand by introducing a methyl group at the middle carbon of 5c. Periodical 1H NMR measurements in DMSO-d6 were performed to monitor the stability of the complexes for longer periods in air, and the catalytic activity of the synthesized compounds was investigated by the deprotection of an alloxycarbonyl (alloc)-protected fluorescent coumarin dye, as monitored by an increase in fluorescence intensity. Modification of the allyl ligand had no effect on the stability, but modification of the Cp ligand was shown to affect the stability of the dissolved complex and, in the case of Cp*, significantly prolong it. As expected, the more stable catalysts are catalytically active for a longer period, but as the reaction rate is not as fast, slightly lower or similar overall yields as compared to the original complex were achieved. Preliminary MTT testing of the obtained complexes revealed IC50 values in the low micromolar range.