Cyclodextrin-derived diorganyl tellurides as glutathione peroxidase mimics and inhibitors of thioredoxin reductase and cancer cell growth

J Med Chem. 2004 Jan 1;47(1):233-9. doi: 10.1021/jm030916r.

Abstract

Water-soluble diorganyl tellurides of the alkyl aryl or dialkyl type were prepared by treatment of mono-6-tosyl-beta-cyclodextrin with sodium alkanetellurolates or arenetellurolates or sodium telluride. The novel cyclodextrin-derived organotelluriums were evaluated for their capacity to catalyze the reduction of hydrogen peroxide, tert-butyl hydroperoxide, and cumene hydroperoxide in the presence of glutathione, NADPH, and GSSG-reductase (coupled reductase assay). Cyclodextrins 4d and 4e, carrying 4-(N,N-dimethylamino)phenyltelluro and n-butyltelluro groups, respectively, were the most efficient glutathione peroxidase mimics. Reduction of lipophilic cumene hydroperoxide often proceeded 10-20 times faster than reduction of the more hydrophilic hydroperoxides, which cannot bind into the hydrophobic interior of the cyclodextrin. Thus, it seems that the carbohydrate moiety acts as a binding site for the hydroperoxide substrate. The cyclodextrin derivatives were also evaluated for their capacity to inhibit thioredoxin reductase/thioredoxin and cancer cell growth in culture. IC(50) values for inhibition of thioredoxin or thioredoxin/thioredoxin reductase were in the submicromolar range for the best inhibitors (compounds 4d and 5). Two of the compounds (4c and 5) were found to inhibit the growth of MCF-7 cells in culture with IC(50) values in the low micromolar range.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cell Division / drug effects
  • Cell Line, Tumor
  • Cyclodextrins / chemical synthesis*
  • Cyclodextrins / chemistry
  • Cyclodextrins / pharmacology
  • Drug Screening Assays, Antitumor
  • Glutathione Peroxidase / chemistry*
  • Humans
  • Molecular Mimicry
  • Organometallic Compounds / chemical synthesis*
  • Organometallic Compounds / chemistry
  • Organometallic Compounds / pharmacology
  • Structure-Activity Relationship
  • Tellurium*
  • Thioredoxin-Disulfide Reductase / antagonists & inhibitors*

Substances

  • Antineoplastic Agents
  • Cyclodextrins
  • Organometallic Compounds
  • Glutathione Peroxidase
  • Thioredoxin-Disulfide Reductase
  • Tellurium