期刊
BIOORGANIC CHEMISTRY
卷 121, 期 -, 页码 -出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2022.105660
关键词
Vitamin D; Active forms of vitamin D; Keratinocytes; Biological activity; Receptors for vitamin D
资金
- NIH [1R01AR073004-01A1, R01AR071189-01A1]
- VA merit grant [1I01BX004293-01A1, R21 AI152047-01A1]
This study established new routes for the chemical synthesis of vitamin D-3 and its hydroxy metabolites. The compounds showed similar properties in inhibiting cell proliferation and inducing cell differentiation, as well as effects on T-cell immune activity. They also interacted with nuclear receptors in a similar manner. The findings have important implications for studying the role of these compounds in the immune system and inflammatory diseases.
New and more efficient routes of chemical synthesis of vitamin D-3 (D-3) hydroxy (OH) metabolites, including 20S (OH)D-3, 20S,23S(OH)(2)D-3 and 20S,25(OH)(2)D-3, that are endogenously produced in the human body by CYP11A1, and of 20S,23R(OH)(2)D-3 were established. The biological evaluation showed that these compounds exhibited similar properties to each other regarding inhibition of cell proliferation and induction of cell differentiation but with subtle and quantitative differences. They showed both overlapping and differential effects on T-cell immune activity. They also showed similar interactions with nuclear receptors with all secosteroids activating vitamin D, liver X, retinoic acid orphan and aryl hydrocarbon receptors in functional assays and also as indicated by molecular modeling. They functioned as substrates for CYP27B1 with enzymatic activity being the highest towards 20S,25(OH)2D(3) and the lowest towards 20S(OH)D-3. In conclusion, defining new routes for large scale synthesis of endogenously produced D3-hydroxy derivatives by pathways initiated by CYP11A1 opens an exciting era to analyze their common and differential activities in vivo, particularly on the immune system and inflammatory diseases.
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