Photoactive Ruthenium Nitrosyls as NO Donors: How To Sensitize Them toward Visible Light

Abstract

Nitric oxide (NO) can induce apoptosis (programmed cell death) at micromolar or higher doses. Although cell death via NO-induced apoptosis has been studied quite extensively, the targeted delivery of such doses of NO to infected or malignant tissues has not been achieved. The primary obstacle is indiscriminate NO release from typical systemic donors such as glycerin trinitrate: once administered, the drug travels throughout the body, and NO is released through a variety of enzymatic, redox, and pH-dependent pathways. Photosensitive NO donors have the ability to surmount this difficulty through the use of light as a localized stimulus for NO delivery. The potential of the method has prompted synthetic research efforts toward new NO donors for use as photopharmaceuticals in the treatment of infections and malignancies. Over the past few years, we have designed and synthesized several metal nitrosyls (NO complexes of metals) that rapidly release NO when exposed to low-power (milliwatt or greater) light of various wavelengths. Among them, the ruthenium nitrosyls exhibit exceptional stability in biological media. However, typical ruthenium nitrosyls release NO upon exposure to UV light, which is hardly suitable for phototherapy. By following a few novel synthetic strategies, we have overcome this problem and synthesized a variety of ruthenium nitrosyls that strongly absorb light in the 400-600-nm range and rapidly release NO under such illumination. In this Account, we describe our progress in designing photoactive ruthenium nitrosyls as visible-light-sensitive NO donors. Our research has shown that alteration of the ligands, in terms of (i) donor atoms, (ii) extent of conjugation, and (iii) substituents on the ligand frames, sensitizes the final ruthenium nitrosyls toward visible light in a predictable fashion. Density functional theory (DFT) and time-dependent DFT (TDDFT) calculations provide guidance in this "smart design" of ligands. We have also demonstrated that direct attachment of dye molecules as light-harvesting antennas also sensitize ruthenium nitrosyls to visible light, and TDDFT calculations provide insight into the mechanisms of sensitization by this technique. The fluorescence of the dye ligands makes these NO donors "trackable" within cellular matrices. Selected ruthenium nitrosyls have been used to deliver NO to cellular targets to induce apoptosis. Our open-design strategies allow the isolation of a variety of these ruthenium nitrosyls, depending on the choices of the ligand frames and dyes. These designed nitrosyls will thus be valuable in the future endeavor of synthesizing novel pharmaceuticals for phototherapy.

The nature of Ru–NO bonds in ruthenium tetraazamacrocycle nitrosyl complexes—a computational study

“…[56][57][58] It should be stressed that controlling the properties of the complex, such as electronic spectra, reduction potential, and specific rate constant of the release of NO, is crucial for biological applications. [15][16][17][18][19][20][21][22][23]37,38,[59][60][61][62][63] Tetraazamacrocycles such as cyclam and its derivatives are fairly flexible; they adopt five different configurations, depending on the spatial alignment of the NH protons (Fig. 1).…”

Nanophotonics and supramolecular chemistry

“…In particular, development of a fluorescent probe for Ca 2+ ion detection fura-2 6 by Tsien and coworkers [43] promoted significant activity in the corresponding research field. , and Zn 2+ have also been developed [44][45][46][47][48] as well as probes for small molecules such as nitrogen monooxide (NO) [49,50]. Another important milestone in biological imaging is the application of green fluorescence protein (GFP) to cell media [51][52][53], which lead to the Nobel prize in Chemistry being awarded to Chalfie, Tsien, and Shimomura in 2008.…”

A multifunctional β-cyclodextrin-conjugate photodelivering nitric oxide with fluorescence reporting

“…However, the biological effects of NO are strictly depending on its concentration, location and dose (Jia et al, 2002). This has made the light-activated NO donors very appealing due to the superb spatiotemporal accuracy the light triggering offers (Ford, 2008;Sortino, 2010;Fry and Mascharak, 2011;Ford, 2013). Several NO photodonors (NOPD) have been supramolecularly combined with CDs derivatives (Fraix et al, 2016).…”