Rational design, synthesis, and biological activity of novel conformationally restricted vitamin D analogues, (22R)- and (22S)-22-ethyl-1,25-dihydroxy-23,24-didehydro-24a,24b-dihomo-20-epivitamin D(3).
Rational design, synthesis, and biological activity of novel conformationally restricted vitamin D analogues, (22R)- and (22S)-22-ethyl-1,25-dihydroxy-23,24-didehydro-24a,24b-dihomo-20-epivitamin D(3).
复制标题
新型构象限制性维生素 D 类似物 (22R)- 和 (22S)-22-乙基-1,25-二羟基-23,24-二脱氢-24a,24b-dihomo-20-epivitamin 的合理设计、合成和生物活性
DOI：
--
复制
发表时间：
2002
影响因子：
7.3
通讯作者：
S. Yamada
中科院分区：
文献类型：
--
作者：
H. Masuno;Keiko Yamamoto;Xinxiang Wang;Mihwa Choi;H. Ooizumi;T. Shinki;S. Yamada
我们根据先前提出的活性空间群概念，合理设计了两种新的维生素D类似物，(22R)-和(22S)-22-乙基-1,25-二羟基-23,24-二脱氢-24a,24b-dihomo-20-epivitamin D(3)（3和4）。 3的22R乙基将侧链的迁移性限制在活性空间区域，而4的22S乙基将侧链限制在非活性区域。 C(23)处的双键进一步限制了侧链的灵活性。这些化合物（3和4）是使用原酸酯克莱森重排作为关键步骤合成的。正如预期的那样，22R 异构体 3 在细胞分化方面的功效比 1,25-二羟基维生素 D(3) (1) 高出近 100 倍，尽管其对维生素 D 受体 (VDR) 的亲和力仅为 1 的七分之一。22S 异构体 4 的功效明显低于 3。与定点突变分析相结合的对接研究表明，两个碳延长的侧链类似物 3 可以安装在配体结合中通过采用稳定的构象，将 VDR 的口袋固定住。
Two new vitamin D analogues, (22R)- and (22S)-22-ethyl-1,25-dihydroxy-23,24-didehydro-24a,24b-dihomo-20-epivitamin D(3) (3 and 4), were rationally designed on the basis of the active space group concept previously proposed by us. The 22R ethyl group of 3 restricts the mobility of the side chain to active space regions, whereas the 22S ethyl group of 4 confines the side chain to an inactive region. The double bond at C(23) further restricts the side chain flexibility. These compounds (3 and 4) were synthesized using ortho ester Claisen rearrangement as the key step. As expected, the 22R isomer 3 has nearly 100 times higher efficacy than 1,25-dihydroxyvitamin D(3) (1) in cell differentiation, although its affinity for the vitamin D receptor (VDR) was one-seventh of that of 1. The 22S isomer 4 has significantly lower efficacy than 3. A docking study in combination with site-directed mutation analysis revealed that two carbon elongated side chain analogue 3 could be fitted in the ligand binding pocket of the VDR by adopting a stable conformation.