Diaryl chalcogenides as selective inhibitors of thioredoxin reductase and potential antitumor agents.
Thioredoxin reductase is a selenocysteine containing flavoenzyme that catalyzes the NADPH dependent reduction of the redox protein thioredoxin. Thioredoxin is over-expressed by a number of human tumors. Experimental studies have shown that thioredoxin is responsible for the growth and transformed phenotype of some human cancer cells. Thus, thioredoxin reductase presents an attractive target for anticancer drug development to regulate the activity of the thioredoxin system. We have examined a series of 12 organoselenium compounds and 16 organotellurium compounds, mostly of the diaryl chalcogenide type, as inhibitors of human thioredoxin reductase and have investigated the cytotoxicity and antitumor activity of some of the compounds. The organoselenium compound Ebselen was found to be a competitive inhibitor of human thioredoxin reductase (Ki 2.8 microM), while a number of organotellurium compounds were found to be noncompetitive inhibitors (Kis 2.3 to 35.2 microM). Human glutathione reductase was not appreciably inhibited by any of the compounds, except for one dinitro organotellurium compound that caused inhibition with an IC50 of 0.5 microM and an over 20-fold selectivity compared to thioredoxin reductase. The compounds inhibited the growth of human cancer cells in culture with IC50s as low as 2 microM Some organotellurium compounds when administered daily by intraperitoneal injection to mice caused up to 50% inhibition of the growth of MCF-7 human breast cancer xenografts but the relative insolubility of the compounds was a limiting factor in their use.
Engman
L
L
Department of Organic Chemistry, Uppsala University, Sweden.
Cotgreave
I
I
Angulo
M
M
Taylor
C W
CW
Paine-Murrieta
G D
GD
Powis
G
G
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001667:Binding, Competitive; D001943:Breast Neoplasms / Q000188:drug therapy*; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007700:Kinetics; D051379:Mice; D008819:Mice, Nude; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D016566:Organoselenium Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D012643:Selenium; D013329:Structure-Activity Relationship; D013691:Tellurium; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009942:Organometallic Compounds; D016566:Organoselenium Compounds; D013880:Thioredoxin-Disulfide Reductase; D012643:Selenium; D013691:Tellurium