Cyclodextrin-derived diorganyl tellurides as glutathione peroxidase mimics and inhibitors of thioredoxin reductase and cancer cell growth.
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.
McNaughton
Michael
M
Department of Organic Chemistry, Institute of Chemistry, Uppsala University, Box 599, S-751 24 Uppsala, Sweden.
Engman
Lars
L
Birmingham
Anne
A
Powis
Garth
G
Cotgreave
Ian A
IA
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D003505:Cyclodextrins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005979:Glutathione Peroxidase / Q000737:chemistry*; D006801:Humans; D018716:Molecular Mimicry; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013691:Tellurium; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D003505:Cyclodextrins; D009942:Organometallic Compounds; D005979:Glutathione Peroxidase; D013880:Thioredoxin-Disulfide Reductase; D013691:Tellurium