Photoactive ruthenium nitrosyls derived from quinoline- and pyridine-based ligands: Accelerated photorelease of NO due to quinoline ligation

Abstract

The ruthenium nitrosyl [(PaPy₂Q)Ru(NO)](BF₄)₂, derived from the quinoline-based ligand PaPy₂QH (PaPy₂QH = N,N-bis(2-pyridylmethyl)amine-N-ethyl-2-quinaldine-2-carboxamide; H = dissociable proton) has been synthesized and characterized by X-ray crystallography and spectroscopic techniques. This {Ru–NO}⁶ nitrosyl is soluble in aqueous media and stable under physiological conditions at pH 7. [(PaPy₂Q)Ru(NO)]²⁺ releases NO rapidly upon exposure to low-intensity UV light (5 mW/cm²). The NO donor capacity of this nitrosyl (quantum yield = 0.20, λ_irr = 365 nm) is considerably higher than that of analogous nitrosyl derived from a polypyridyl ligand without the quinoline moiety.

Introduction

Nitric oxide (NO) is an important signaling molecule that participates in many biological processes including blood pressure regulation, immune response, cell apoptosis, and tumor metastasis [1], [2], [3], [4], [5], [6], [7], [8]. Consequently, there has been much interest in developing novel NO donors as both therapeutic agents and research tools in biology [9]. Over the years, many NO donors have been synthesized and characterized for such uses and several classes of NO donors such as organic nitrites, nitrosothiols and diazeniumdiolates (NONOates) have found therapeutic use [9], [10], [11]. Most of these NO donors are activated by ubiquitous stimuli like heat, changes in pH, or certain enzymes. As a result, these drugs are mostly systemic and cannot be employed for target-specific delivery. In recent years, attention has been diverted to one emerging type of NO donors that can be activated by light [12]. This class of photochemotherapeutics includes inorganic metal complexes of NO (metal nitrosyls) that release NO upon exposure to light [13]. These NO donors are of special interest because of their potential use in photodynamic therapy (PDT) for cancer [14]. In previous work, we have described several designed iron [15], [16], [17], manganese [18] and ruthenium [19] nitrosyls that rapidly release NO upon illumination. For example, the two nitrosyls [(PaPy₃)Fe(NO)]²⁺ and [(PaPy₃)Ru(NO)]²⁺, derived from the designed ligand N,N-bis(2-pyridylmethyl)amine-N-ethyl-2-pyridine-2-carboxamide (PaPy₃H, H = dissociable proton) [20] exhibit excellent NO photolability when exposed to low-energy visible and UV light respectively. As shown below, the PaPy₃H ligand contains a carboxamide group that binds the metal center through the carboxamido-N following deprotonation. Our work has established that coordination of the carboxamido-N conjugated to the pyridine ring is a major determinant of the NO photolability of these nitrosyls.

The {Ru–NO}⁶ nitrosyl [(PaPy₃)Ru(NO)](BF₄)₂ exhibits great stability in aqueous solution over a wide range of pH (3–11) for long periods of time. We have employed this nitrosyl to successfully deliver NO to biological targets such as myoglobin, cytochrome c oxidase and soluble guanylate cyclase under controlled conditions of illumination [18], [21], [22]. In order to further improve the NO donating capacity of this NO donor, we recently decided to increase the extent of conjugation in the carboxamide arm of the ligand. We hypothesized that the greater light-harvesting properties of the quinoline moiety (versus pyridine) might enhance the photolability of the Ru–NO unit. In such attempt, we have now synthesized the ligand N,N-bis(2-pyridylmethyl)amine-N-ethyl-2-quinaldine-2-carboxamide (PaPy₂QH) that contains a quinoline group in place of pyridine [23]. In this paper we report the synthesis, structure and properties of the {Ru–NO}⁶ nitrosyl [(PaPy₂Q)Ru(NO)](BF₄)₂. This nitrosyl indeed exhibits improved photoefficiency when exposed to low-intensity (mW) UV light.