Synthesis of 6-anilino-2-thiouracils and their inhibition of human placenta iodothyronine deiodinase.
Several 6-anilino-2-thiouracils were synthesized and tested for their ability to inhibit the inner-ring iodothyronine deiodinase from human placenta. The p-ethyl and p-n-butyl analogues were strongly inhibitory to the enzyme and were much more effective than the standard deiodinase inhibitor, 6-propyl-2-thiouracil. The degree of inhibition caused by 6-(p-n-butylanilino)-2-thiouracil was, moreover, unaffected by high concentrations of reducing agent in the enzyme assay. Attempts to prepare 3-alkyl derivatives via S-debenzylation of 2-benzylthio intermediates led to rearrangement to, for example, 3-methyl-5-benzyl-6-amino-2-thiouracil. This compound also strongly inhibited the deiodinase reaction. Preliminary results suggest that these compounds are useful to study in vitro and in vivo metabolism of thyroid hormones and may be clinically useful to enhance the availability of active thyroid hormones to certain organs.
D055598:Chemical Phenomena; D002621:Chemistry; D004229:Dithiothreitol / Q000494:pharmacology; D005260:Female; D006801:Humans; D007453:Iodide Peroxidase / Q000037:antagonists & inhibitors*; D010920:Placenta / Q000201:enzymology*; D011247:Pregnancy; D011441:Propylthiouracil / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013889:Thiouracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
D013889:Thiouracil; D011441:Propylthiouracil; D007453:Iodide Peroxidase; D004229:Dithiothreitol