Biomimetic Studies on Iodothyronine Deiodinase Intermediates: Modeling the Reduction of Selenenyl Iodide by Thiols

Abstract

Enzyme mimetic studies on the crucial intermediate (E-SeI) of the iodothyronine deiodinase cycle have been carried out by using an areneselenenyl iodide stabilized by intramolecular Se.N interactions. Treatment of this compound with aromatic thiols and thiobenzoxazole in the presence of NEt(3) affords areneselenenyl sulfides that are stable towards disproportionation reactions. The structures of three of the areneselenenyl sulfides were determined by X-ray crystallography. In one case, in the absence of NEt(3), a diselenide can be formed rather than the selenenyl sulfide. The areneselenenyl iodide also reacts with a related selenol to produce the corresponding diselenide, and this reaction is found to be much faster than that with thiols. The high reactivity of the selenenyl iodide with the selenol suggests that a reduced selenol group (R'-SeH) may react with the E-SeI intermediate to produce a diselenide (E-Se-Se-R') without any thiol cosubstrate. The intermediacy of selenenyl sulfides during the reduction of selenenyl iodide by thiols and its possible relevance to the iodothyronine deiodinase catalytic cycle is also described.

Structural aspects of some organoselenium compounds

“…The Se···N distance in 7 is 2.636 (2) Å and is longer than the single bond covalent radii (1.87 Å) but considerably shorter than the sum of their van der Waals radii (3.5 Å). The Se···N bond distance is slightly longer than the selenenylsulfide based on 4,4-dimethyl-2-phenyl-2-oxazoline [2.617(2) Å] having a five-membered heterocyclic ring [17]. On the other hand, the Se···N distance in 7 is significantly larger than the selenenylsulfide of 2-phenyl-2-oxazine [2.458(2) Å] having a six-membered heterocyclic ring [3].…”

The role of the halogen bond in iodothyronine deiodinase: Dependence on chalcogen substitution in naphthyl‐based mimetics

“…ID‐1 and ID‐3, instead, work through a mechanism of inner‐ring deiodination (IRD) and are involved in the deactivation of T3, forming either the inactive isomer 3,3′,5′‐triiodothyronine (rT3) from T4, or removing an iodine from T3, generate the 3,3′‐diiodothyronine (3,3′‐T2) . The high regioselectivity shown by different deiodinases concentrated a great deal of efforts in the development of low molecular mass compounds that mimic the native isoforms of deiodinases, aiming at both understanding the mechanism of action of the enzymes and synthesize therapeutic agents able to control thyroid hormone levels, fundamental to several essential processes …”

“…In the last two decades, Mugesh and coworkers synthesized a series of organochalcogens as functional mimics of deiodinases, focusing on peri ‐substituted naphthalenes, containing thiol and selenol groups (Scheme ) . In particular, naphthyl‐based compounds bearing a thiol‐selenol pair ( 1 ) or two thiols ( 2 ) respectively exhibited inferior deiodinase activity in the inner‐ring deiodination of T4 under relevant physiological conditions with respect to compound 3 , having two selenol moieties in peri ‐position.…”

Modeling of the 5′‐Deiodination of Thyroxine by Iodothyronine Deiodinase: Chemical Corroboration of a Selenenyl Iodide Intermediate

“…Although there have been several reports of the reaction of 2,6‐diiodophenol derivatives with organoselenols,3a,b the formation of the corresponding selenenyl iodide intermediates has never been detected. The verification of the process in Equation (1) has been difficult not only because of the instability of selenenyl iodides,5 but also as a result of the high reactivity of selenenyl iodides toward selenols 3c. Herein, we report experimental evidence for the formation of a selenenyl iodide in 5′‐deiodination of a thyroxine derivative by an organoselenol, through the use of a nanosized molecular cavity to stabilize the selenenyl iodide intermediate. …”