Structure Elucidation and Characterization of Different Thyroxine Polymorphs

Mondal, Santanu; Mugesh, Govindasamy

doi:10.1002/ange.201505281

Cited by 15 publications

(3 citation statements)

References 36 publications

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“…A similar profile is detected for both formulations, although with an onset slightly shifted to lower temperatures: ∆T ons ~50 The calorimetric analysis (Figure 3b-c) seems to confirm the dehydration behavior found by TGA: a multiple endotherm profile, attributed to the removal of adsorbed and coordinated water, is detected from ~35 to ~140 • C for neat T4. The registered thermogram is in accordance with previous studies [28,29], but the temperature location is shifted due to different water contents. A closer inspection of the cryogenic temperature range shows crystal-crystal transitions in T4 (−40 • C on cooling and −34 • C upon heating), coherent with polymorphism.…”

Section: Characterization Of T4-ilssupporting

confidence: 89%

“…A closer inspection of the cryogenic temperature range shows crystal-crystal transitions in T4 (−40 • C on cooling and −34 • C upon heating), coherent with polymorphism. In fact, it is already reported in the literature that [Na][T4] can exist in distinct polymorphic forms [29,30]. It is worthwhile noting that the conversion between polymorphs is reversible, as proved by their detection in the first two cycles carried out up to 40 • C (see the inset of Figure 3b), a temperature insufficient to promote water evaporation.…”

Section: Characterization Of T4-ilsmentioning

confidence: 56%

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Ionic Levothyroxine Formulations: Synthesis, Bioavailability, and Cytotoxicity Studies

Barreira

Santos

Dionı́sio

et al. 2023

IJMS

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Thyroid diseases affect a considerable portion of the population, with hypothyroidism being one of the most commonly reported thyroid diseases. Levothyroxine (T4) is clinically used to treat hypothyroidism and suppress thyroid stimulating hormone secretion in other thyroid diseases. In this work, an attempt to improve T4 solubility is made through the synthesis of ionic liquids (ILs) based on this drug. In this context, [Na][T4] was combined with choline [Ch]+ and 1-(2-hydroxyethyl)-3-methylimidazolium [C2OHMiM] + cations in order to prepare the desired T4-ILs. All compounds were characterized by NMR, ATR-FTIR, elemental analysis, and DSC, aiming to check their chemical structure, purities, and thermal properties. The serum, water, and PBS solubilities of the T4-ILs were compared to [Na][T4], as well as the permeability assays. It is important to note an improved adsorption capacity, in which no significant cytotoxicity was observed against L929 cells. [C2OHMiM][T4] seems to be a good alternative to the commercial levothyroxine sodium salt with promising bioavailability.

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Section: Characterization Of T4-ilssupporting

confidence: 89%

Section: Characterization Of T4-ilsmentioning

confidence: 56%

Ionic Levothyroxine Formulations: Synthesis, Bioavailability, and Cytotoxicity Studies

Barreira

Santos

Dionı́sio

et al. 2023

IJMS

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“…Strikingly, compounds 4 and 5 bearing one or two tellurium atoms mediated the removal of all four iodine atoms from T4 to produce T0, although the rate of 5‐deiodination of T4 was found to be much higher than that of 5′‐deiodination [6c] . While the reactivity of chalcogen atom in deiodinase mimetics and substrate conformation appear to play important roles in the deiodination, [5,6c–e] it is still not clear how the enzymes control the regioselectivity of this important biological reaction using selenium at the active site. In this paper, we show that the regioselectivity of deiodination mediated by deiodinase mimics can be changed dramatically by altering the electronic properties of the iodine atoms through substitution at the phenolic group of T4 under physiological conditions.…”

Section: Introductionmentioning

confidence: 99%

A Simple Substitution on Thyroid Hormones Remarkably Alters the Regioselectivity of Deiodination by a Deiodinase Mimic

Giri

Raja

Mugesh

2022

Chemistry A European J

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The regioselective deiodinations of L-thyroxine (T4) play key roles in the thyroid hormone homeostasis. These reactions are catalyzed by three isoforms of the selenoenzymes, iodothyronine deiodinases (Dio1, Dio2 and Dio3), which are highly homologous in nature. Dio1 mediates 5'-or 5-deiodinations of T4 to produce T3 and rT3, respectively. In contrast, Dio2 and Dio3 are selective to 5'-or 5-deiodination to produce T3 and rT3, respectively. Understanding of the regioselectivity of deiodination at the molecular level is important as abnormal levels of thyroid hormone have been implicated in various clinical conditions, such as hypoxia, myocardial infarction, neuronal ischemia and cancer. In this paper, we report that the electronic properties of the iodine atoms in thyroxine (T4) can be modulated through a simple substitution in the 4'-phenolic moiety. This leads to the change in the regioselectivity of deiodination by different small molecule mimics of Dio enzymes. By using this chemical approach, we also show that the substitution of a strong electron withdrawing group facilitates the removal of all four iodine atoms in the T4 derivative. Theoretical investigations on the hydrogen bonded adducts of T4 with imidazole indicate that the charge on the iodine atoms depend on the nature of hydrogen bond between the À OH group of T4 and the imidazole moiety. While the imidazole can act as either hydrogen bond acceptor (HBA) or hydrogen bond donor (HBD), the protonated imidazole acts exclusively as HBD in T4-imidazole complex. These studies support the earlier observations that the histidine residue at the active sites of the deiodinases play an important role not only in the substrate binding, but also in altering the regioselectivity of the deiodination reactions.

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Schilddrüsenhormone – von der Kristallstruktur über die Aktivität zur Reaktivität

Schweizer

Steegborn

2015

Angewandte Chemie

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Bereits geringe Abweichungen der individuellen Schilddrü-senhor monwerte wirken sich negativ auf das kçrperliche Wohlbefinden aus.E ine T4-Ersatztherapie ist für Tausende Patienten notwendig, denen jedes Jahr die Schilddrüse entfernt wird, sowie für Millionen hypothyreote Patienten, die T4 zur TSH-Suppression bençtigen. l-T4 wird in Tablettenform verabreicht. Dabei wird stillschweigend angenommen, dass das schlecht wasserlçsliche Molekül irgendwie aus der Tablette freigesetzt und während der Darmpassage aufgenommen wird. ¾rzte wissen, dass ihre Patienten mit Nachdruck an einem einmal verordneten T4-Präparat festhalten. Obwohl man sich nicht erklären kann, weshalb 100 mgv on synthetisch reinem Thyroxin der einen Marke nicht mit 100 mgreinem Thyroxin einer anderen Marke äquivalent sein sollten, berücksichtigen gegenwärtige Richtlinien den Wunsch der Patienten. [3] Der kürzlich erschienene Artikel von Mondal und Mugesh über molekulare Eigenschaften des Thyroxins liefert eine erstaunlich einfache Antwort auf dieses Mysterium. [4] Die Autoren kristallisierten synthetisches Thyroxin aus verschiedenen Lçsungsmitteln und fanden zweierlei Kristallformen:e ine trikline (Form I) und eine monokline (Form II). Beide Polymorphe enthielten jeweils zwei Moleküle T4 in der asymmetrischen Einheit, die zudem in verschiedenen Konformationen vorlagen und unterschiedliche intra-und intermolekulare Wechselwirkungen im Kristallgitter eingingen. Die Unterschiede betrafen insbesondere die Orientierung der Amino-und Carboxygruppen zum Diphenyletherrest sowie Abbildung 1. Strukturen und Nummerierung des ProhormonsThyroxin und seines aktiveren Metaboliten T3. Die Affinität des nukleären T3-Rezeptors zu T3 ist mehr als zehnmal hçher als die zu T4. Der Tyrosylring, der die 3-und 5-Iodatome trägt, wird oft als "innerer Ring" bezeichnet, während der Phenolring "äußerer Ring" genannt wird.

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Structure Elucidation and Characterization of Different Thyroxine Polymorphs

Cited by 15 publications

References 36 publications

Ionic Levothyroxine Formulations: Synthesis, Bioavailability, and Cytotoxicity Studies

Ionic Levothyroxine Formulations: Synthesis, Bioavailability, and Cytotoxicity Studies

A Simple Substitution on Thyroid Hormones Remarkably Alters the Regioselectivity of Deiodination by a Deiodinase Mimic

Schilddrüsenhormone – von der Kristallstruktur über die Aktivität zur Reaktivität

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