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.

碘甲状腺原氨酸脱碘酶（Iodothyronine deiodinases, IDs）是一类哺乳动物源性硒酶，可分别通过外环脱碘途径（outer-ring deiodination pathways）与内环脱碘途径（inner-ring deiodination pathways），催化甲状腺素（thyroxine, T4）转化为3,5,3'-三碘甲状腺原氨酸（3,5,3′-triiodothyronine, T3）与3,3',5'-三碘甲状腺原氨酸（3,3′,5′-triiodothyronine, rT3）。该类酶还可进一步催化T3与rT3的脱碘反应，生成多种二碘与单碘甲状腺原氨酸衍生物。本文报道了一系列带有不同氨基取代基的peri-取代萘（peri-substituted naphthalenes）的脱碘酶活性。这类化合物可选择性地从T4与T3的内环脱去碘原子，分别生成rT3与3,3'-二碘甲状腺原氨酸（3,3′-diiodothyronine, 3,3'-T2）。在peri-位点带有两个硒醇基的萘基化合物，其脱碘酶活性远高于带有两个巯基或一个巯基-硒醇对（thiol–selenol pair）的同类化合物。机理研究表明，碘原子与硫族元素（chalcogen, S或Se）之间形成的卤键（halogen bond），以及两个硫族原子间的peri-相互作用（硫键, chalcogen bond），对脱碘反应至关重要。尽管卤键的形成会导致C-I键的伸长，但硫键可促进更多电子密度向C-I σ*轨道（σ* orbitals）转移，最终实现C-I键的完全断裂。氨基取代硒类化合物活性更高的原因，可归因于氨基可使巯基/硒醇基团（thiol/selenol moiety）发生去质子化（deprotonation），这一过程不仅增强了卤键的强度，同时也促进了硫族-硫族相互作用。