The molecular design of S-nitrosothiols as photodynamic agents for controlled nitric oxide release.
Nitric oxide is a small messenger molecule utilized by nature in cell signalling and the non-specific immune response. At present, nitric oxide releasing prodrugs cannot be efficiently targeted towards a specific body compartment, which restricts their therapeutic applications. To address this limitation, we have designed two photolabile nitric oxide releasing prodrugs, tert-butyl S-nitrosothiol and tert-dodecane S-nitrosothiol, which are based on the S-nitrosothiol functionality. By modulating the prodrugs' hydrophobicity, we postulated that we could increase their stability within the cell by preventing their interaction with hydrophilic thiols and metal ions; processes that are known to inactivate this prodrug class. Our data demonstrate that these prodrugs have improved nitric oxide release kinetics compared to currently available S-nitrosothiols, as they are highly stable in vitro in the absence of irradiation (t(1/2) > 3 h), while their rate of decomposition can be regulated by controlling the intensity or duration of the photostimulus. Nitric oxide release can readily be achieved using non-laser based light sources, which enabled us to characterize photoactivation as a trigger mechanism for nitric oxide release in A549 lung carcinoma cells. Here we confirmed that irradiation induced highly significant increases in cytotoxicity within a therapeutic drug range (1-100 μm), and the utility of this photoactivation switch opens up avenues for exploring the applications of these prodrugs for chemical biology studies and chemotherapy.
Department of Pharmacology and Toxicology, Otago School of Medical Sciences, University of Otago, Dunedin, New Zealand.
Niroshini M
NM
Giles
Sweta
S
Kumari
Bevan P
BP
Gang
Chun W W
CW
Yuen
Emilie M F
EM
Billaud
Gregory I
GI
Giles
D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003692:Delayed-Action Preparations / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D056004:Molecular Dynamics Simulation; D009569:Nitric Oxide / Q000008:administration & dosage* / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000737:chemistry* / Q000494:pharmacology; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000737:chemistry* / Q000494:pharmacology; D011355:Prodrugs / Q000737:chemistry* / Q000494:pharmacology; D026403:S-Nitrosothiols / Q000737:chemistry* / Q000494:pharmacology
D003692:Delayed-Action Preparations; D020030:Nitric Oxide Donors; D017319:Photosensitizing Agents; D011355:Prodrugs; D026403:S-Nitrosothiols; D009569:Nitric Oxide