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研究 20S-羟基维生素 D 类似物及其 1α-OH 衍生物作为具有抗炎活性的强效维生素 D 受体激动剂。

Investigation of 20S-hydroxyvitamin D analogs and their 1α-OH derivatives as potent vitamin D receptor agonists with anti-inflammatory activities.

机构信息

Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, 38163, United States.

Department of Chemistry, University of Pennsylvania, Philadelphia, PA, 19104, United States.

出版信息

Sci Rep. 2018 Jan 24;8(1):1478. doi: 10.1038/s41598-018-19183-7.

DOI:10.1038/s41598-018-19183-7
PMID:29367669
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5784132/
Abstract

20S-hydroxyvitamin D [20S(OH)D] is anti-inflammatory and not hypercalcemic, suggesting its potential as a lead compound. In this study, side chain modified 20S(OH)D 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)D, 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)D scaffold for the development of novel anti-inflammatory agents.

摘要

20S-羟基维生素 D [20S(OH)D] 具有抗炎作用且不会引起高钙血症，这表明它有作为先导化合物的潜力。在这项研究中，侧链修饰的 20S(OH)D 类似物（4、13、23 和 33）及其 1α-OH 衍生物被合成，并测试了它们的代谢和生物学活性。4、13 和 23 是 CYP27B1 的良好底物，能够酶促合成它们的 1α-OH 衍生物 5、14 和 24。然而，33 不能被 CYP27B1 羟化，并且作为抑制剂起作用。与骨化三醇相比，所有类似物都是 CYP24A1 较差的底物，表明代谢稳定性得到改善。虽然母体类似物对 VDR 的刺激活性很小，但它们的 1α-OH 衍生物是有效的 VDR 激动剂。4、5、14 和 24 显著上调 CYP24A1 在 mRNA 水平的表达，与它们的 VDR 激活能力一致，并表明 1α-羟化是产生具有强活性的类似物所必需的。这些类似物具有抗炎活性，其受侧链组成和 1α-羟化的影响。为了了解它们与 VDR 的分子相互作用，20S(OH)D、4 和 33 与 VDR 配体结合域共结晶，这揭示了与骨化三醇结合的受体的细微差异。这项研究表明 20S(OH)D 支架具有开发新型抗炎剂的潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/69b7/5784132/6344a4f6abff/41598_2018_19183_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/69b7/5784132/562db865cb26/41598_2018_19183_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/69b7/5784132/d592fddbfcb8/41598_2018_19183_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/69b7/5784132/8fe190274aa6/41598_2018_19183_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/69b7/5784132/b058039c578e/41598_2018_19183_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/69b7/5784132/8499dbf0bcd5/41598_2018_19183_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/69b7/5784132/78274d9b1d1e/41598_2018_19183_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/69b7/5784132/7e0d92e465b3/41598_2018_19183_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/69b7/5784132/6344a4f6abff/41598_2018_19183_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/69b7/5784132/562db865cb26/41598_2018_19183_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/69b7/5784132/d592fddbfcb8/41598_2018_19183_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/69b7/5784132/8fe190274aa6/41598_2018_19183_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/69b7/5784132/b058039c578e/41598_2018_19183_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/69b7/5784132/8499dbf0bcd5/41598_2018_19183_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/69b7/5784132/78274d9b1d1e/41598_2018_19183_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/69b7/5784132/7e0d92e465b3/41598_2018_19183_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/69b7/5784132/6344a4f6abff/41598_2018_19183_Fig8_HTML.jpg

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