抗甲状腺药物及其类似物:合成、结构和作用机理。
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吗哪D, Roy G, Mugesh G
抗甲状腺药物及其类似物:合成、结构和作用机理。
Acc化学研究》2013年11月19日,46(11):2706 - 15所示。doi: 10.1021 / ar4001229。Epub 2013年7月24日。
- PubMed ID
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23883148 (在PubMed]
- 文摘
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甲状腺激素是必不可少的发展人体的所有细胞和分化。调节蛋白质、脂肪和碳水化合物的新陈代谢。在这个帐户,我们将讨论的合成、结构和甲状腺激素的作用机制及其类似物。激素原的甲状腺素(T4)是合成甲状腺球蛋白的甲状腺过氧化物酶(TPO),使用碘的血红素酶和过氧化氢进行碘化和酚醛耦合反应。3 ',T4 monodeiodination 3 5-triiodothyronine (T3) selenium-containing deiodinases(符合id 2)是一个关键步骤在甲状腺激素的激活。类型3 deiodinase (id 3)催化失活过程中的甲状腺激素去除碘有选择地从T4的酪氨酰环产生3,3 ',5 '三碘甲状腺氨酸(rT3)。几个生理和病理刺激影响甲状腺激素合成。甲状腺激素的生产过剩导致甲状腺机能亢进,由抗甲状腺药物治疗抑制甲状腺激素的生物合成和/或减少T4, T3的转换。抗甲状腺药物thiourea-based化合物,包括丙基硫氧嘧啶(PTU)、甲硫咪唑(MMI)和卡比马唑(卡马西平)。甲状腺积极集中这些杂环化合物浓度梯度。 Recently, the selenium analogues of PTU, MMI, and CBZ attracted significant attention because the selenium moiety in these compounds has a higher nucleophilicity than that of the sulfur moiety. Researchers have developed new methods for the synthesis of the selenium compounds. Several experimental and theoretical investigations revealed that the selone (C horizontal lineSe) in the selenium analogues is more polarized than the thione (C horizontal lineS) in the sulfur compounds, and the selones exist predominantly in their zwitterionic forms. Although the thionamide-based antithyroid drugs have been used for almost 70 years, the mechanism of their action is not completely understood. Most investigations have revealed that MMI and PTU irreversibly inhibit TPO. PTU, MTU, and their selenium analogues also inhibit ID-1, most likely by reacting with the selenenyl iodide intermediate. The good ID-1 inhibitory activity of PTU and its analogues can be ascribed to the presence of the -N(H)-C( horizontal lineO)- functionality that can form hydrogen bonds with nearby amino acid residues in the selenenyl sulfide state. In addition to the TPO and ID-1 inhibition, the selenium analogues are very good antioxidants. In the presence of cellular reducing agents such as GSH, these compounds catalytically reduce hydrogen peroxide. They can also efficiently scavenge peroxynitrite, a potent biological oxidant and nitrating agent.
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