Regioselective Deiodination of Thyroxine by Iodothyronine Deiodinase Mimics: An Unusual Mechanistic Pathway Involving Cooperative Chalcogen and Halogen Bonding

Iodothyronine deiodinases (IDs) are mammalian selenoenzymes
that
catalyze the conversion of thyroxine (T4) to 3,5,3′-triiodothyronine
(T3) and 3,3′,5′-triiodothyronine (rT3) by the outer-
and inner-ring deiodination pathways, respectively. These enzymes
also catalyze further deiodination of T3 and rT3 to produce a variety
of di- and monoiodo derivatives. In this paper, the deiodinase activity
of a series of peri-substituted naphthalenes having
different amino groups is described. These compounds remove iodine
selectively from the inner-ring of T4 and T3 to produce rT3 and 3,3′-diiodothyronine
(3,3′-T2), respectively. The naphthyl-based compounds having
two selenols in the peri-positions exhibit much higher
deiodinase activity than those having two thiols or a thiol–selenol
pair. Mechanistic investigations reveal that the formation of a halogen
bond between the iodine and chalcogen (S or Se) and the peri-interaction between two chalcogen atoms (chalcogen bond) are important
for the deiodination reactions. Although the formation of a halogen
bond leads to elongation of the C–I bond, the chalcogen bond
facilitates the transfer of more electron density to the C–I
σ* orbitals, leading to a complete cleavage of the C–I
bond. The higher activity of amino-substituted selenium compounds
can be ascribed to the deprotonation of thiol/selenol moiety by the
amino group, which not only increases the strength of halogen bond
but also facilitates the chalcogen–chalcogen interactions.