Fine-Feature Modifications to Strained Ruthenium Complexes Radically Alter Their Hypoxic Anticancer Activity^†.

Area of Science:

• Medicinal Chemistry
• Photodynamic Therapy
• Ruthenium Complexes

Background:

• Earlier studies revealed significant biological activity differences between structural isomers of π-expansive ruthenium complexes.
• These complexes are investigated for photodynamic and photochemotherapy applications.

Purpose of the Study:

• To explore the activity of functionalized derivatives of previously studied ruthenium complex isomers.
• To investigate the impact of structural modifications on photocytotoxicity under normoxic and hypoxic conditions.

Main Methods:

• Synthesis and testing of functionalized derivatives of 1-NIP and 2-NIP ruthenium isomers.
• Evaluation of photocytotoxicity under normoxic and hypoxic conditions.
• Measurement of singlet oxygen sensitization quantum yield and photosubstitution rates.

Main Results:

• Functionalization with methyl or methoxy groups restored photocytotoxicity to the inactive 2-NIP isomer.
• Methoxy variants of the active 1-NIP isomer became inactive.
• Singlet oxygen sensitization quantum yield remained below 1% for all compounds.
• Hypoxic photocytotoxicity was generally attenuated, with few active compounds.

Conclusions:

• Minor structural modifications on non-strained ligands dramatically modulate the normoxic and hypoxic activity of strained ruthenium complexes.
• These structural changes influence photocytotoxicity more than singlet oxygen sensitization or photosubstitution rates in cell-free conditions.