Low toxicity β-cyclodextrin-caged 4,4'-bipyridinium-bis(siloxane): synthesis and evaluation

Chem Res Toxicol. 2014 Apr 21;27(4):546-57. doi: 10.1021/tx400407e. Epub 2014 Mar 7.

Abstract

The toxicity of viologens can be significantly reduced by including them in tight [2]rotaxane structures alongside β-cyclodextrin, thus turning them into candidates of pharmaceutical interest. Here, we report a synthesis pathway for a benign viologen, by capping a small β-cyclodextrin-caged molecule, the 4,4'-bipyridine, with minimal-length presynthesized axle-stopper segments of the propyl-3-pentamethyldisiloxane type. After 90 min from the oral administration to laboratory mice, the product concentration in the bloodstream reaches a value equivalent to 0.634% of the initial dose of 800 mg·kg(-1). As compared to the nude viologen having the same structure, which proved to be lethal in doses of 40 mg·kg(-1), the product induces reversible morphological changes in the liver, kidney, lung, and cerebellum, up to a dose of 400 mg·kg(-1), with higher dosages giving rise to a chronic slow evolution.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Cerebellum / drug effects
  • Kidney / drug effects
  • Liver / drug effects
  • Lung / drug effects
  • Mice
  • Proton Magnetic Resonance Spectroscopy
  • Pyridines / chemistry
  • Pyridines / toxicity*
  • Siloxanes / chemical synthesis
  • Siloxanes / chemistry
  • Siloxanes / toxicity*
  • beta-Cyclodextrins / chemistry*

Substances

  • Pyridines
  • Siloxanes
  • beta-Cyclodextrins
  • betadex
  • 4,4'-bipyridyl