Investigation of 20S-hydroxyvitamin D(3) analogs and their 1α-OH derivatives as potent vitamin D receptor agonists with anti-inflammatory activities.
Investigation of 20S-hydroxyvitamin D(3) analogs and their 1α-OH derivatives as potent vitamin D receptor agonists with anti-inflammatory activities.
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研究20S-羟基维生素D（3）类似物及其1α-OH衍生物是具有抗炎活性的有效维生素D受体激动剂。
DOI：
10.1038/s41598-018-19183-7
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发表时间：
2018-01-24
影响因子：
4.6
通讯作者：
Li W
中科院分区：
文献类型：
--
作者：
Lin Z;Marepally SR;Goh ESY;Cheng CYS;Janjetovic Z;Kim TK;Miller DD;Postlethwaite AE;Slominski AT;Tuckey RC;Peluso-Iltis C;Rochel N;Li W
20S-羟基维生素D3[20S(OH)D3]是抗炎和不高钙的，这表明它可能是一种先导化合物。本研究合成了侧链修饰的20S(OH)D3类似物(4、13、23和33)及其1α-OH衍生物，并对它们的代谢和生物活性进行了测试。4、13和23是细胞色素P27B1的良好底物，使酶促合成其1α-OH衍生物5、14和24成为可能。但33不能被CYP27B1羟化，起到了抑制作用。所有类似物对CYP24A1的底物都比骨化三醇差，这表明分解代谢的稳定性得到了改善。虽然母体类似物对维生素D受体的刺激活性很低，但它们的1α-OH衍生物是有效的维生素D受体激动剂。4、5、14和24在基因水平显著上调细胞色素P24A1的表达，这与它们激活维生素D受体的能力一致，表明需要1α-羟基化才能产生具有较强活性的类似物。这些类似物具有抗炎活性，其活性受侧链组成和1-α-羟基化的影响。为了了解它们与VDR的分子相互作用，20S(OH)D3、4和33与VDR配体结合域共结晶，揭示了与骨化三醇结合受体的细微差异。本研究展示了20S(OH)D3支架在开发新型抗炎药方面的潜力。
20S-hydroxyvitamin D3 [20S(OH)D3] is anti-inflammatory and not hypercalcemic, suggesting its potential as a lead compound. In this study, side chain modified 20S(OH)D3 analogs (4, 13, 23 and 33) together with their 1α-OH derivatives were synthesized and their metabolism and biological activities tested. 4, 13 and 23 are good substrates for CYP27B1, enabling enzymatic synthesis of their 1α-OH derivatives 5, 14 and 24. However, 33 could not be hydroxylated by CYP27B1 and acts as an inhibitor. All analogs were poorer substrates for CYP24A1 than calcitriol, indicating improved catabolic stability. While the parent analogs showed minimal VDR stimulating activity, their 1α-OH derivatives were potent VDR agonists. 4, 5, 14 and 24 significantly upregulated the expression of CYP24A1 at the mRNA level, consistent with their VDR activation abilities and indicating that 1α-hydroxylation is required to produce analogs with strong activity. These analogs have anti-inflammatory activities that are influenced by side chain composition and by 1α-hydroxylation. To understand their molecular interactions with the VDR, 20S(OH)D3, 4 and 33 were co-crystalized with the VDR ligand binding domain, which revealed subtle differences to the calcitriol-bound receptor. This study demonstrates the potential of the 20S(OH)D3 scaffold for the development of novel anti-inflammatory agents.
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DOI：
10.1016/j.jsbmb.2014.11.010
发表时间：
2015-07
期刊：
The Journal of steroid biochemistry and molecular biology
影响因子：
--
作者：
Slominski AT;Li W;Kim TK;Semak I;Wang J;Zjawiony JK;Tuckey RC
通讯作者：
Tuckey RC
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
8.8
作者：
Janjetovic, Z.;Brozyna, A. A.;Slominski, A. T.
通讯作者：
Slominski, A. T.
影响因子：
2.7
作者：
Li, Wei;Chen, Jianjun;Slominski, Andrzej
通讯作者：
Slominski, Andrzej
影响因子：
3.7
作者：
Slominski AT;Janjetovic Z;Fuller BE;Zmijewski MA;Tuckey RC;Nguyen MN;Sweatman T;Li W;Zjawiony J;Miller D;Chen TC;Lozanski G;Holick MF
通讯作者：
Holick MF