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.

Glutathione Peroxidase (GPx)-like Antioxidant Activity of the Organoselenium Drug Ebselen: Unexpected Complications with Thiol Exchange Reactions

“…The theoretical data 28 obtained under the present study are in good agreement with the experimental results. For example, bond lengths and angles obtained by theoretical calculations for 13 are consistent with the data obtained from single-crystal X-ray analysis . The calculated GIAO 77 Se NMR chemical shifts for most of the compounds in the present study also correlate well with the experimental data.…”

Glutathione Peroxidase (GPx)-like Antioxidant Activity of the Organoselenium Drug Ebselen: Unexpected Complications with Thiol Exchange Reactions

“…The theoretical data 28 obtained under the present study are in good agreement with the experimental results. For example, bond lengths and angles obtained by theoretical calculations for 13 are consistent with the data obtained from single-crystal X-ray analysis . The calculated GIAO 77 Se NMR chemical shifts for most of the compounds in the present study also correlate well with the experimental data.…”

Chelate Ring Size Effect on the Reactivity of [2-(2-Phenyl-5,6-dihydro-4H-1,3-oxazinyl)]lithium and Se···N Interactions in Low-Valent Organoselenium Compounds: Facile Isolation of Diorganotriselenide

“…The Se−S distance is 2.2495(6) Å, which is similar to the reported distances for selenenyl sulfides [2.22176(6)−2.2416(6) Å] based on 4,4-dimethyl-2-phenyloxazoline 13b. The C(1)−Se−S angle is 100.36(6)°, which is well within the range of reported corresponding angles (100−104°) 13b 4 Molecular structure of 29 . …”

“…The Se···N intramolecular distance in 29 (2.458(2) Å) is longer than that observed for selenenyl halides ( 25 − 27 ). The Se···N distance in 29 is significantly shorter than corresponding distances for reported organylselenenyl sulfides [2.617(2)−2.590(2) Å] 13b. The Se−S distance is 2.2495(6) Å, which is similar to the reported distances for selenenyl sulfides [2.22176(6)−2.2416(6) Å] based on 4,4-dimethyl-2-phenyloxazoline 13b.…”

“…The Se···N distance in 29 is significantly shorter than corresponding distances for reported organylselenenyl sulfides [2.617(2)−2.590(2) Å] 13b. The Se−S distance is 2.2495(6) Å, which is similar to the reported distances for selenenyl sulfides [2.22176(6)−2.2416(6) Å] based on 4,4-dimethyl-2-phenyloxazoline 13b. The C(1)−Se−S angle is 100.36(6)°, which is well within the range of reported corresponding angles (100−104°) 13b…”

Iodo(trisyl)sulfane: Reactivity of a Stable Alkanesulfenyl Iodide towards Antithyroid Drugs

“…The MMI‐derived unsymmetric disulfide 6 , which lacks a hydrogen‐bond donor, is a monomer. N ‐Methylation,1 and/or the absence of hydrogen‐bonding dimers in conjunction with facile thiol‐exchange reactions of the MMI‐selenosulfide derivative,7,8 have been proposed as possible explanations for the inactivity of MMI towards deiodinase (ID‐1) inhibition. The monomeric structure of disulfide 6 , which is homologous to the MMI‐selenosulfide derivative, supports this hypothesis.…”

Glutathione Peroxidase (GPx)-like Antioxidant Activity of the Organoselenium Drug Ebselen: Unexpected Complications with Thiol Exchange Reactions

“…The theoretical data 28 obtained under the present study are in good agreement with the experimental results. For example, bond lengths and angles obtained by theoretical calculations for 13 are consistent with the data obtained from single-crystal X-ray analysis . The calculated GIAO 77 Se NMR chemical shifts for most of the compounds in the present study also correlate well with the experimental data.…”

Chelate Ring Size Effect on the Reactivity of [2-(2-Phenyl-5,6-dihydro-4H-1,3-oxazinyl)]lithium and Se···N Interactions in Low-Valent Organoselenium Compounds: Facile Isolation of Diorganotriselenide

“…The Se−S distance is 2.2495(6) Å, which is similar to the reported distances for selenenyl sulfides [2.22176(6)−2.2416(6) Å] based on 4,4-dimethyl-2-phenyloxazoline 13b. The C(1)−Se−S angle is 100.36(6)°, which is well within the range of reported corresponding angles (100−104°) 13b 4 Molecular structure of 29 . …”

“…The Se···N intramolecular distance in 29 (2.458(2) Å) is longer than that observed for selenenyl halides ( 25 − 27 ). The Se···N distance in 29 is significantly shorter than corresponding distances for reported organylselenenyl sulfides [2.617(2)−2.590(2) Å] 13b. The Se−S distance is 2.2495(6) Å, which is similar to the reported distances for selenenyl sulfides [2.22176(6)−2.2416(6) Å] based on 4,4-dimethyl-2-phenyloxazoline 13b.…”

“…The Se···N distance in 29 is significantly shorter than corresponding distances for reported organylselenenyl sulfides [2.617(2)−2.590(2) Å] 13b. The Se−S distance is 2.2495(6) Å, which is similar to the reported distances for selenenyl sulfides [2.22176(6)−2.2416(6) Å] based on 4,4-dimethyl-2-phenyloxazoline 13b. The C(1)−Se−S angle is 100.36(6)°, which is well within the range of reported corresponding angles (100−104°) 13b…”

Iodo(trisyl)sulfane: Reactivity of a Stable Alkanesulfenyl Iodide towards Antithyroid Drugs

“…The MMI‐derived unsymmetric disulfide 6 , which lacks a hydrogen‐bond donor, is a monomer. N ‐Methylation,1 and/or the absence of hydrogen‐bonding dimers in conjunction with facile thiol‐exchange reactions of the MMI‐selenosulfide derivative,7,8 have been proposed as possible explanations for the inactivity of MMI towards deiodinase (ID‐1) inhibition. The monomeric structure of disulfide 6 , which is homologous to the MMI‐selenosulfide derivative, supports this hypothesis.…”

Glutathione Peroxidase (GPx)-like Antioxidant Activity of the Organoselenium Drug Ebselen: Unexpected Complications with Thiol Exchange Reactions

“…The theoretical data 28 obtained under the present study are in good agreement with the experimental results. For example, bond lengths and angles obtained by theoretical calculations for 13 are consistent with the data obtained from single-crystal X-ray analysis . The calculated GIAO 77 Se NMR chemical shifts for most of the compounds in the present study also correlate well with the experimental data.…”

Chelate Ring Size Effect on the Reactivity of [2-(2-Phenyl-5,6-dihydro-4H-1,3-oxazinyl)]lithium and Se···N Interactions in Low-Valent Organoselenium Compounds: Facile Isolation of Diorganotriselenide

“…The Se−S distance is 2.2495(6) Å, which is similar to the reported distances for selenenyl sulfides [2.22176(6)−2.2416(6) Å] based on 4,4-dimethyl-2-phenyloxazoline 13b. The C(1)−Se−S angle is 100.36(6)°, which is well within the range of reported corresponding angles (100−104°) 13b 4 Molecular structure of 29 . …”

“…The Se···N intramolecular distance in 29 (2.458(2) Å) is longer than that observed for selenenyl halides ( 25 − 27 ). The Se···N distance in 29 is significantly shorter than corresponding distances for reported organylselenenyl sulfides [2.617(2)−2.590(2) Å] 13b. The Se−S distance is 2.2495(6) Å, which is similar to the reported distances for selenenyl sulfides [2.22176(6)−2.2416(6) Å] based on 4,4-dimethyl-2-phenyloxazoline 13b.…”

“…The Se···N distance in 29 is significantly shorter than corresponding distances for reported organylselenenyl sulfides [2.617(2)−2.590(2) Å] 13b. The Se−S distance is 2.2495(6) Å, which is similar to the reported distances for selenenyl sulfides [2.22176(6)−2.2416(6) Å] based on 4,4-dimethyl-2-phenyloxazoline 13b. The C(1)−Se−S angle is 100.36(6)°, which is well within the range of reported corresponding angles (100−104°) 13b…”

Iodo(trisyl)sulfane: Reactivity of a Stable Alkanesulfenyl Iodide towards Antithyroid Drugs

“…The MMI‐derived unsymmetric disulfide 6 , which lacks a hydrogen‐bond donor, is a monomer. N ‐Methylation,1 and/or the absence of hydrogen‐bonding dimers in conjunction with facile thiol‐exchange reactions of the MMI‐selenosulfide derivative,7,8 have been proposed as possible explanations for the inactivity of MMI towards deiodinase (ID‐1) inhibition. The monomeric structure of disulfide 6 , which is homologous to the MMI‐selenosulfide derivative, supports this hypothesis.…”