Thioredoxin reductase and cancer cell growth inhibition by organotellurium compounds that could be selectively incorporated into tumor cells.
The thioredoxins are small ubiquitous redox proteins with the conserved redox catalytic sequence-Trp-Cys-Gly-Pro-Cys-Lys, where the Cys residues undergo reversible NADPH dependent reduction by selenocysteine containing flavoprotein thioredoxin reductases. Thioredoxin expression is increased in several human primary cancers including lung, colon, cervix, liver, pancreatic, colorectal and squamous cell cancer. The thioredoxin/thioredoxin reductase pathway therefore provides an attractive target for cancer drug development. Organotellurium steroid, lipid, amino acid, nucleic base, and polyamine inhibitors were synthesized on the basis that they might be selectively or differentially incorporated into tumor cells. Some of the newly prepared classes of tellurium-based inhibitors (lipid-like compounds 3b and 3e, amino acid derivative 5b, nucleic base derivative 8b, and polyamine derivatives 14a and 14b) inhibited TrxR/Trx and cancer cell growth in culture with IC(50) values in the low micromolar range.
Engman
Lars
L
Department of Organic Chemistry, Institute of Chemistry, Uppsala University, PO Box 599, S-751 24, Uppsala, Sweden. lars.engman@kemi.uu.se
Al-Maharik
Nawaf
N
McNaughton
Michael
M
Birmingham
Anne
A
Powis
Garth
G
D002455:Cell Division / Q000187:drug effects*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D013691:Tellurium / Q000378:metabolism / Q000494:pharmacology*; D013880:Thioredoxin-Disulfide Reductase / Q000378:metabolism*
D013880:Thioredoxin-Disulfide Reductase; D013691:Tellurium