Piano-Stool Ruthenium(II) Complexes with Delayed Cytotoxic Activity: Origin of the Lag Time.

Area of Science:

• Organometallic Chemistry
• Medicinal Chemistry
• Coordination Chemistry

Background:

• Previously reported piano-stool ruthenium(II) complexes with pyrenyl phosphine ligands exhibited significant cytotoxic activity.
• The current study investigates the impact of steric hindrance from a bulky phosphine ligand, diisopropyl(1-pyrenyl)phosphane (L), on ruthenium(II) complex behavior.

Purpose of the Study:

• To synthesize and characterize new ruthenium(II) complexes with varying arene and halide ligands.
• To evaluate the effect of steric bulk in the phosphine ligand on ligand exchange reactions and cytotoxic activity.
• To elucidate the mechanism behind the observed lag time in cytotoxicity for aged solutions.

Main Methods:

• Synthesis of four new ruthenium(II) complexes: [RuCl2(mba)(L)], [RuI2(mba)(L)], [RuCl2(p-cym)(L)], and [RuI2(p-cym)(L)].
• Cytotoxicity assays after 24h incubation with cells.
• Spectroscopic and analytical characterization of synthesized and aged complexes, including the isolation of cyclometalated species.

Main Results:

• Newly synthesized complexes initially displayed poor cytotoxic activity.
• Aged solutions of [RuI2(p-cym)(L)] and [RuCl2(p-cym)(L)] showed enhanced activity over time.
• Transformation in DMSO led to the formation of cyclometalated ruthenium species, which were isolated and characterized.
• The cyclometalated complexes ([RuCl(p-cym)(κ2C-L)], [RuI(p-cym)(κ2C-L)], and [Ru(p-cym)(κS-dmso)(κ2C-L)]PF6) exhibited potent cytotoxic activity.

Conclusions:

• Steric hindrance in the phosphine ligand influences the stability and reactivity of ruthenium(II) complexes in DMSO.
• DMSO facilitates the transformation of non-cyclometalated complexes into highly cytotoxic cyclometalated ruthenium species.
• The formation of cyclometalated species is responsible for the delayed but potent cytotoxic effect observed in aged solutions.