Duggan B M, Craik D J
School of Pharmaceutical Chemistry, Victorian College of Pharmacy, Monash University, Parkville, Victoria, Australia.
J Med Chem. 1997 Jul 4;40(14):2259-65. doi: 10.1021/jm9606610.
1H NMR spectra of the thyroid hormone thyroxine recorded at low temperature and high field show splitting into two peaks of the resonance due to the H2,6 protons of the inner (tyrosyl) ring. A single resonance is observed in 600 MHz spectra at temperatures above 185 K. An analysis of the line shape as a function of temperature shows that the coalescence phenomenon is due to an exchange process with a barrier of 37 kJ mol-1. This is identical to the barrier for coalescence of the H2',6' protons of the outer (phenolic) ring reported previously for the thyroid hormones and their analogues. It is proposed that the separate peaks at low temperature are due to resonances for H2,6 in cisoid and transoid conformers which are populated in approximately equal populations. These two peaks are averaged resonances for the individual H2 and H6 protons. Conversion of cisoid to transoid forms can occur via rotation of either the alanyl side chain or the outer ring, from one face of the inner ring to the other. It is proposed that the latter process is the one responsible for the observed coalescence phenomenon. The barrier to rotation of the alanyl side chain is > or = 37 kJ mol-1, which is significantly larger than has previously been reported for Csp2-Csp3 bonds in other Ph-CH2-X systems. The recent crystal structure of a hormone agonist bound to the ligand-binding domain of the rat thyroid hormone receptor (Wagner et al. Nature 1995, 378, 690-697) shows the transoid form to be the bound conformation. The significant energy barrier to cisoid/transoid interconversion determined in the current study combined with the tight fit of the hormone to its receptor suggests that interconversion between the forms cannot occur at the receptor site but that selection for the preferred bound form occurs from the 50% population of the transoid form in solution.
在低温和高场条件下记录的甲状腺激素甲状腺素的1H NMR谱显示，由于内环（酪氨酰）环的H2,6质子，共振分裂为两个峰。在温度高于185 K时，600 MHz谱中观察到单一共振。对线形随温度变化的分析表明，合并现象是由于具有37 kJ mol-1势垒的交换过程。这与先前报道的甲状腺激素及其类似物外环（酚环）的H2',6'质子合并的势垒相同。有人提出，低温下的单独峰是由于顺式和反式构象中H2,6的共振，它们的数量大致相等。这两个峰是各个H2和H6质子的平均共振。顺式向反式形式的转化可以通过丙氨酰侧链或外环从内环的一个面旋转到另一个面来实现。有人提出，后一过程是观察到的合并现象的原因。丙氨酰侧链旋转的势垒≥37 kJ mol-1，这比先前报道的其他Ph-CH2-X系统中Csp2-Csp3键的势垒要大得多。最近一种与大鼠甲状腺激素受体配体结合域结合的激素激动剂的晶体结构（Wagner等人，《自然》，1995年，378卷，690 - 697页）表明反式形式是结合构象。在本研究中确定的顺式/反式相互转化的显著能垒，结合激素与其受体的紧密结合，表明在受体部位不能发生形式之间的相互转化，但对优选结合形式的选择发生在溶液中50%反式形式的群体中。
