Effect of Halogen Substitution on the Regioselective Deiodination of Thyroid Hormone Analogues by Deiodinase Mimics.

The deiodination of L-thyroxine (T4) by the three isoforms of selenium-containing iodothyronine deiodinases (DIOs) is an important process in the human body for the maintenance of the thyroid hormone homeostasis. The 5'-deiodination of T4 by DIO1 or DIO2 produces the biologically active hormone 3,5,3'-triiodo thyronine (T3) and 5-deiodination by DIO1 or DIO3 generates 3,3',5'-triiodo thyronine (rT3), which is considered to be biologically inactive. Selenium compounds are known to mimic the function of DIO3 by catalyzing the 5-deiodination of T4 and a co-operative halogen and chalcogen bonding is responsible for their activity. The substitution of 4'-OH group of T4 by an electron withdrawing group not only alters the reactivity but also changes the regioselectivity of deiodination. However, the effect of other halogen atoms (F, Cl or Br) in place of iodine in T4 on the regioselectivity has not been explored. In this paper, we describe simple synthetic methodologies toward various halogen analogues of T4. We also show that 2D NMR spectroscopy can be used as a powerful tool to identify the location of various halogen substitutions on the phenolic or tyrosyl rings. The deiodination experiments with peri-substituted naphthalene diselenol reveal that the regioselectivity or specificity towards iodine atom is not altered upon introduction of more electronegative halogen atoms (F, Cl and Br), reinforcing the concept of halogen bonding in the deiodination reactions.