The molecular design of S-nitrosothiols as photodynamic agents for controlled nitric oxide release

Chem Biol Drug Des. 2012 Sep;80(3):471-8. doi: 10.1111/j.1747-0285.2012.01420.x. Epub 2012 Jun 28.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Death / drug effects
  • Cell Line, Tumor
  • Delayed-Action Preparations / chemistry*
  • Delayed-Action Preparations / pharmacology
  • Drug Design
  • Humans
  • Molecular Dynamics Simulation
  • Nitric Oxide / administration & dosage*
  • Nitric Oxide / pharmacology
  • Nitric Oxide Donors / chemistry*
  • Nitric Oxide Donors / pharmacology
  • Photochemotherapy
  • Photosensitizing Agents / chemistry*
  • Photosensitizing Agents / pharmacology
  • Prodrugs / chemistry*
  • Prodrugs / pharmacology
  • S-Nitrosothiols / chemistry*
  • S-Nitrosothiols / pharmacology

Substances

  • Delayed-Action Preparations
  • Nitric Oxide Donors
  • Photosensitizing Agents
  • Prodrugs
  • S-Nitrosothiols
  • Nitric Oxide