Acetylacetonate Ruthenium Nitrosyls: A Gateway to Nitric Oxide Release in Water under Near-Infrared Excitation by Two-Photon Absorption.

A fundamental challenge for phototriggered therapies is to obtain robust molecular frameworks that can withstand biological media. Photoactivatable nitric oxide (NO) releasing molecules (photoNORMs) based on ruthenium nitrosyl (RuNO) complexes are among the most studied systems due to several appealing features that make them attractive for therapeutic applications. Nevertheless, the propensity of the NO ligand to be attacked by nucleophiles frequently manifests as significant instability in water for this class of photoNORMs. Our approach to overcome this limitation involved enhancing the Ru-NO π-backbonding to lower the electrophilicity at the NO by replacing the commonly employed 2,2'-bipyridine (bpy) ligand by an anionic, electron-rich, acetylacetonate (acac). A versatile and convenient synthetic route is developed and applied for the preparation of a large library of RuNO photoNORMs with the general formula [RuNO(tpy)(acac)]2+ (tpy = 2,2':6',2″-terpyridine). A combined theoretical and experimental analysis of the Ru-NO bonding in these complexes is presented, supported by extensive single-crystal X-ray diffraction experiments and by topological analyses of the electron charge density by DFT. The enhanced π-back-bonding, systematically evidenced by several techniques, resulted in a remarkable stability in water for these complexes, where significant NO release efficiencies were recorded. We finally demonstrate the possibility of obtaining sophisticated water-stable multipolar NO-delivery platforms that can be activated in the near-IR region by two-photon absorption (TPA), as demonstrated for an octupolar complex with a TPA cross section of 1530 GM at λ = 800 nm and for which NO photorelease was demonstrated under TPA irradiation in aqueous media.

Ruthenium nitrosyl complexes with NO release capability: the use of fluorene as an antenna.

A ruthenium nitrosyl complex of formula [RuII(fluorene(C6)CH2O-terpy)(bipy)(NO)]3+ (AC) in which fluorene(C6) is the 9,9-dihexylfluorene, terpy the 2,2';6',2''-terpyridine, and bipy the 2,2'-bipyridine is presented with its related [RuII(MeO-terpy)(bipy)(NO)]3+ (C) and 9,9-dihexylfluorene 2-hydroxymethylfluorene (A) building blocks. The reference complex C undergoes NO release capabilities under irradiation at λ = 365 nm. The effect of the introduction of the fluorescent A antenna within the resulting AC complex is discussed both experimentally and theoretically. The importance of the encaging parameter defined as ϕAC·IAC, in which IAC is the quantity of light absorbed by AC and ϕAC the quantum yield of NO release is evidenced and found to be concentration dependent. The conditions of optimization of the antenna approach to maximize ϕAC·IAC are discussed. The crystal structure of [RuII(fluorene(C6)CH2O-terpy)(bipy)(NO2)](PF6), the last intermediate in the synthesis of AC is also presented.