Structure over States: Planarity, Not Energy, Dictates Photoactivation in Ru(II) PACT Agents

Area of Science:

• Inorganic Chemistry
• Photochemistry
• Computational Chemistry

Background:

• Photoactivated chemotherapy (PACT) uses light to control drug activity, minimizing side effects.
• Ruthenium(II) polypyridyl complexes are promising PACT agents, but predicting their light-induced reactions is difficult.
• Existing computational methods struggle to explain observed photosubstitution yields.

Purpose of the Study:

• To develop and validate a novel computational protocol for simulating Ru(II) photosubstitution reactions.
• To elucidate the mechanistic factors governing photosubstitution efficiency in Ru(II) complexes for PACT.
• To provide a predictive tool for designing next-generation photoresponsive anticancer agents.

Main Methods:

• Synthesis of nine Ru(II) complexes with varying bidentate ligands.
• Red-light irradiation experiments in aqueous solution to measure photosubstitution quantum yields.
• Development of a triplet-state molecular dynamics protocol using GFN-xTB, explicit solvation, and enhanced sampling.

Main Results:

• The novel computational method successfully simulated ligand exchange processes and distinguished photoactive from photoinactive compounds.
• Photosubstitution quantum yields were found to be highly dependent on the deviation from planarity of the bidentate ligand, not excited state energies.
• Both cis and trans substitution pathways were identified, and the reaction mechanism (dissociative, interchange, or associative) was determined for each complex.

Conclusions:

• Ligand non-planarity is a key factor in Ru(II) photosubstitution efficiency, promoting the trans pathway.
• The developed computational protocol offers mechanistic insights and a scalable tool for designing improved PACT agents.
• This work advances the understanding of Ru(II) photochemistry and aids in the rational design of targeted cancer therapies.