Water-soluble trithiolato-bridged dinuclear ruthenium(II) and osmium(II) arene complexes with bisphosphonate functionalized ligands as anticancer organometallics

Trithiolato-bridged dinuclear ruthenium(II) complexes [Ru2(p-cym)2(SR)3]Cl (p-cym = p-cymene, R = benzyl derivatives) are regarded as the most cytotoxically potent metal(II) arene antineoplastics, but are oftentimes limited by their poor solubility in aqueous media. Thus, we designed bisphosphonate-functionalized ligands for use in a modular two-step complexation process to synthesize six trithiolato-bridged dinuclear ruthenium(II) and osmium(II) arene complexes bearing one to three bisphosphonate-benzylmercaptane derived ligands. In addition to improved aqueous solubility the high affinity of bisphosphonates towards apatite structures found in bone and bone metastases may grant selective targeting properties to functionalized organometallics. The complex stabilities and hydroxyapatite binding behavior were determined by UV/Vis spectroscopy. The bisphosphonate functionalization decreases antiproliferative activity in vitro, which was correlated to lower cellular accumulation, due to the different lipophilic profiles of the drug candidates. Synopsis: The bisphosphonate functionalized organometallics of this work show enhanced affinity towards bone model substrate hydroxyapatite. [Display omitted] •Preparation of bisphosphonate-functionalized benzyl thiolate ligands•Establishment of water-soluble trithiolato-bridged dinuclear organometallics•Complexes were stable over 24 h under physiological relevant conditions.•Observation of uptake dependent cytotoxicity•Complexes show affinity towards hydroxyapatite bone model substrate.