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Investigation of 20S-hydroxyvitamin D3 analogs and their 1?-OH derivatives as potent vitamin D receptor agonists with anti-inflammatory activities.

ABSTRACT: 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 1?-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 1?-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 1?-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 1?-hydroxylation is required to produce analogs with strong activity. These analogs have anti-inflammatory activities that are influenced by side chain composition and by 1?-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.

SUBMITTER: Lin Z

PROVIDER: S-EPMC5784132 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Publications

Investigation of 20S-hydroxyvitamin D3 analogs and their 1α-OH derivatives as potent vitamin D receptor agonists with anti-inflammatory activities.

Lin Zongtao Z Marepally Srinivasa R SR Goh Emily S Y ESY Cheng Chloe Y S CYS Janjetovic Zorica Z Kim Tae-Kang TK Miller Duane D DD Postlethwaite Arnold E AE Slominski Andrzej T AT Tuckey Robert C RC Peluso-Iltis Carole C Rochel Natacha N Li Wei W

Scientific reports 20180124 1

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 CYP27 ...[more]

PMID: 29367669

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Project description:The physiological relevance C-3 epimer of 25-hydroxyvitamin D (3-epi-25(OH)D) is not well understood among youth. The objective of this study was to assess whether demographic/physiologic characteristics were associated with 3-epi-25(OH)D3 concentrations in youth. Associations between 3-epi-25(OH)D3 and demographics and between 3-epi-25(OH)D3, total 25-hydroxyvitamin (25(OH)D) (25(OH)D2 + 25(OH)D3), total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglycerides were examined in racially/ethnically diverse schoolchildren (n = 682; age, 8-15 years) at Boston-area urban schools. Approximately 50% of participants had detectable 3-epi-25(OH)D3 (range 0.95-3.95 ng/mL). The percentage of 3-epi-25(OH)D3 of total 25(OH)D ranged from 2.5% to 17.0% (median 5.5%). Males were 38% more likely than females to have detectable 3-epi-25(OH)D3 concentrations. Both Asian and black race/ethnicity were associated with lower odds of having detectable 3-epi-25(OH)D3 compared with non-Hispanic white children (Asian vs. white, odds ratio (OR) 0.28, 95% confidence interval (CI) 0.14-0.53; black vs. white, OR 0.38, 95%CI 0.23-0.63, p < 0.001). Having an adequate (20-29 ng/mL) or optimal (>30 ng/mL) 25(OH)D concentration was associated with higher odds of having detectable 3-epi-25(OH)D3 than having an inadequate (<20 ng/mL) concentration (OR 4.78, 95%CI 3.23-6.94 or OR 14.10, 95%CI 7.10-28.0, respectively). There was no association between 3-epi-25(OH)D3 and blood lipids. However, when considering 3-epi-25(OH)D3 as a percentage of total 25(OH)D, total cholesterol was lower in children with percent 3-epi-25(OH)D3 above the median (mean difference -7.1 mg/dL, p = 0.01). In conclusion, among schoolchildren, sex, race/ethnicity, and total serum 25(OH)D concentration is differentially associated with 3-epi-25(OH)D. The physiological relevance of 3-epi-25(OH)D3 may be related to the 3-epi-25(OH)D3 as a percentage of total 25(OH)D and should be considered in future investigations.

Dataset Information

Investigation of 20S-hydroxyvitamin D3 analogs and their 1?-OH derivatives as potent vitamin D receptor agonists with anti-inflammatory activities.

Publications

Investigation of 20S-hydroxyvitamin D<sub>3</sub> analogs and their 1α-OH derivatives as potent vitamin D receptor agonists with anti-inflammatory activities.

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