643090-93-1Relevant articles and documents
Biomimetic deiodination of thyroid hormones and iodothyronamines-a structure-activity relationship study
Mondal, Santanu,Mugesh, Govindasamy
supporting information, p. 9490 - 9500 (2016/10/22)
Mammalian selenoenzymes, iodothyronine deiodinases (DIOs), catalyze the tyrosyl and phenolic ring deiodination of thyroid hormones (THs) and play an important role in maintaining the TH concentration throughout the body. These enzymes also accept the decarboxylated thyroid hormone metabolites, iodothyronamines (TAMs), as substrates for deiodination. Naphthalene-based selenium and/or sulphur-containing small molecules have been shown to mediate the regioselective tyrosyl ring deiodination of thyroid hormones and their metabolites. Herein, we report on the structure-activity relationship studies of a series of peri-substituted selenium-containing naphthalene derivatives for the deiodination of thyroid hormones and iodothyronamines. Single crystal X-ray crystallographic and 77Se NMR spectroscopic studies indicated that the intramolecular Se?X (X = N, O and S) interactions play an important role in the deiodinase activity of the synthetic mimics. Furthermore, the decarboxylated metabolites, TAMs, have been observed to undergo slower tyrosyl ring deiodination than THs by naphthyl-based selenium and/or sulphur-containing synthetic deiodinase mimics and this has been explained on the basis of the strength of Se?I halogen bonding formed by THs and TAMs.
Regioselective deiodination of iodothyronamines, endogenous thyroid hormone derivatives, by deiodinase mimics
Mondal, Santanu,Mugesh, Govindasamy
, p. 11120 - 11128,9 (2014/11/27)
Iodothyronine deiodinases (IDs) are mammalian selenoenzymes that play an important role in the activation and inactivation￡ of thyroid hormones. It is known that iodothyronamines (TnAMs), produced by the decarboxylation of thyroid hormones, act as substrates for deiodinases. To understand whether decarboxylation alters the rate and/or regioselectivity of deiodination by using synthetic deiodinase mimics, we studied the deiodination of different iodothyronamines. The triiodo derivative 3,3,5-triiodothyronamine (T3 AM) is deiodinated at the inner ring by naphthyl-based deiodinase mimics, which is similar to the deiodination of 3,3,5-triiodothyronine (T3). However, T3 AM undergoes much slower deiodination than T3. Detailed experimental and theoretical investigations suggest that T3 AM forms a weaker halogen bond with selenium donors than T3. Kinetic studies and single-crystal X-ray structures of T3 and T3 AM reveal that intermolecular I...I interactions may play an important role in deiodination. The formation of hydrogen- and halogen-bonding assemblies, which leads to the formation of a dimeric species of T3 in solution, facilitates the interactions between the selenium and iodine atoms. In contrast, T3 AM, which does not have I...I interactions, undergoes much slower deiodination.
Characterization of thyroid hormone receptor α (TRα)-specific analogs with varying inner- and outer-ring substituents
Ocasio, Cory A.,Scanlan, Thomas S.
, p. 762 - 770 (2008/09/17)
Analogs of the TRα-specific thyromimetic CO23 were synthesized and analyzed in vitro using competitive binding and transactivation assays. Like CO23, all analogs bind to both thyroid hormone receptor subtypes with about the same affinity; however, modification of CO23 by derivatization of the 3′ position of the outer-ring or replacement of the inner-ring iodides with bromides attenuates binding. Despite lacking a preference in binding to TRα, all analogs display TRα-specificity in transactivation assays using U2OS and HeLa cells. At best, several agonists exhibit an approximately 6-12-fold preference in transactivation when tested with TRα in HeLa cells. One analog, CO24, showed in vivo TRα-specific action in a tadpole metamorphosis assay.
