Chemical synthesis of 20S-hydroxyvitamin D3, which shows antiproliferative activity
Open accessAbstract
20S-hydroxyvitamin D3 (20S-(OH)D3), an in vitro product of vitamin D3 metabolism by the cytochrome P450scc, was recently isolated, identified and shown to possess antiproliferative activity without inducing hypercalcemia. The enzymatic production of 20S-(OH)D3 is tedious, expensive, and cannot meet the requirements for extensive chemical and biological studies. Here we report for the first time the chemical synthesis of 20S-(OH)D3 which exhibited biological properties characteristic of the P450scc-generated compound. Specifically, it was hydroxylated to 20,23-dihydroxyvitamin D3 and 17,20-dihydroxyvitamin D3 by P450scc and was converted to 1alpha,20-dihydroxyvitamin D3 by CYP27B1. It inhibited proliferation of human epidermal keratinocytes with lower potency than 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3) in normal epidermal human keratinocytes, but with equal potency in immortalized HaCaT keratinocytes. It also stimulated VDR gene expression with similar potency to 1,25(OH)2D3, and stimulated involucrin (a marker of differentiation) and CYP24 gene expression, showing a lower potency for the latter gene than 1,25(OH)2D3. Testing performed with hamster melanoma cells demonstrated a dose-dependent inhibition of cell proliferation and colony forming capabilities similar or more pronounced than those of 1,25(OH)2D3. Thus, we have developed a chemical method for the synthesis of 20S-(OH)D3, which will allow the preparation of a series of 20S-(OH)D3 analogs to study structure-activity relationships to further optimize this class of compound for therapeutic use.
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20(OH)D3 produced by CYP11A1 is the 20S epimer.
“NMR analysis and chemical synthesis have revealed that this product is the 20S epimer”
From The role of CYP11A1 in the production of vitamin D metabolites and their role in the regulation of epidermal functions (2014) · cites this paper as [49]
20(OH)D3 and 20,23(OH)2D3 inhibit DNA synthesis and colony formation, cause cell cycle arrest, and stimulate keratinocyte differentiation with potency comparable to 1,25(OH)2D3.
“These secosteroids inhibit DNA synthesis and colony formation, cause cell cycle arrest and stimulate the differentiation program of keratinocytes with a potency comparable to that of 1,25(OH)2D3.”
From The role of CYP11A1 in the production of vitamin D metabolites and their role in the regulation of epidermal functions (2014) · cites this paper as [49]
CYP11A1 favors initial hydroxylation of vitamin D3 at C20 over C22 (or C23), with 20(OH)D3 as the first and major metabolite.
“Subsequent enzymatic analysis revealed that CYP11A1 favors initial hydroxylation of D3 at C20 over C22 (or C23), with 20(OH)D3 representing the first and major metabolite.”
From Novel activities of CYP11A1 and their potential physiological significance (2015) · cites this paper as [104]
In vitro studies with exogenously added compounds show that novel CYP11A1-derived secosteroids and Δ7-steroids have anti-proliferative, pro-differentiation, and anti-inflammatory effects on cultured skin cells, depending on the compound's structure and the cell lineage.
“Importantly, in vitro studies with exogenously added compounds reveal that novel CYP11A1-derived secosteroids and Δ7steroids exerts anti-proliferative, pro-differentiation, and anti-inflammatory effects on cultured skin cells, which are dependent on the structure of the compound and the cell lineage [57,104,112,114–119].”
From Novel activities of CYP11A1 and their potential physiological significance (2015) · cites this paper as [104]
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References 32 · Cited by 68
Research works printed but not linked: 1
- [33]Slominski AT Products of vitamin D3 or 7-dehydrocholesterol metabolism by cytochrome P450scc show anti-leukemia effects, having low or absent calcemic activity PLoS One 2010 5 3 e9907 20360850 PMC2845617
- Authors
- Li, W., Chen, J., Janjetovic, Z., Kim, T.-K., Sweatman, T., Lu, Y., Zjawiony, J., Tuckey, R. C., Miller, D., & Slominski, A.
- Affiliations
- University of Tennessee Health Science Center (US)
- University of Mississippi (US)
- The University of Western Australia (AU)
- Venue
- Steroids
- Publisher
- Elsevier BV
- Published
- 2010-12
- Volume
- 75
- Issue
- 12
- Pages
- 926-935
- ISSN
- 0039-128X (ISSN-L)
- PMC
- PMC2937189
- OpenAlex
- W2040722453
- Cited by
- 68
- References
- 32
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 4 · 2023: 1 · 2022: 6 · 2021: 6 · 2020: 8 · 2019: 1 · 2018: 3 · 2017: 7 · 2016: 4 · 2015: 5 · 2014: 4 · 2013: 6 · 2012: 8
- FWCI
- 3.68
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Steroids (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R15CA125623)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR-052190, R01AR052190)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Vitamin D Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Steroid Chemistry and Biochemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Natural product bioactivities and synthesis
- Keywords
- chemical synthesis, vitamin D3 metabolism, cytochrome P450scc, CYP27B1, antiproliferative activity, epidermal keratinocytes, HaCaT keratinocytes, involucrin, CYP24, melanoma cells, structure-activity relationship, vitamin D analogs
- MeSH terms
- Animals, Calcifediol, Cholecalciferol, Cholesterol Side-Chain Cleavage Enzyme, Cricetinae, Humans, Models, Molecular, Molecular Conformation, 25-Hydroxyvitamin D3 1-alpha-Hydroxylase, Keratinocytes, Cell Line, Tumor, Cell Proliferation
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