Journal
ACCOUNTS OF CHEMICAL RESEARCH
Volume 44, Issue 4, Pages 289-298Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ar100155t
Keywords
-
Categories
Funding
- NSF [CHE-0553405, CHE-0957251]
- Direct For Mathematical & Physical Scien
- Division Of Chemistry [0957251] Funding Source: National Science Foundation
Ask authors/readers for more resources
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 photo-pharmaceuticals 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available