TY - JOUR
T1 - Chemical synthesis, biological activities and action on nuclear receptors of 20S(OH)D3, 20S,25(OH)2D3, 20S,23S(OH)2D3 and 20S,23R(OH)2D3
AU - Brzeminski, Pawel
AU - Fabisiak, Adrian
AU - Slominski, Radomir M.
AU - Kim, Tae Kang
AU - Janjetovic, Zorica
AU - Podgorska, Ewa
AU - Song, Yuwei
AU - Saleem, Mohammad
AU - Reddy, Sivani B.
AU - Qayyum, Shariq
AU - Song, Yuhua
AU - Tuckey, Robert C.
AU - Atigadda, Venkatram
AU - Jetten, Anton M.
AU - Sicinski, Rafal R.
AU - Raman, Chander
AU - Slominski, Andrzej T.
PY - 2022/4
Y1 - 2022/4
N2 - New and more efficient routes of chemical synthesis of vitamin D3 (D3) hydroxy (OH) metabolites, including 20S(OH)D3, 20S,23S(OH)2D3 and 20S,25(OH)2D3, that are endogenously produced in the human body by CYP11A1, and of 20S,23R(OH)2D3 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)2D3 and the lowest towards 20S(OH)D3. 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.
AB - New and more efficient routes of chemical synthesis of vitamin D3 (D3) hydroxy (OH) metabolites, including 20S(OH)D3, 20S,23S(OH)2D3 and 20S,25(OH)2D3, that are endogenously produced in the human body by CYP11A1, and of 20S,23R(OH)2D3 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)2D3 and the lowest towards 20S(OH)D3. 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.
KW - Active forms of vitamin D
KW - Biological activity
KW - Keratinocytes
KW - Receptors for vitamin D
KW - Vitamin D
UR - http://www.scopus.com/inward/record.url?scp=85124486407&partnerID=8YFLogxK
U2 - 10.1016/j.bioorg.2022.105660
DO - 10.1016/j.bioorg.2022.105660
M3 - Article
C2 - 35168121
AN - SCOPUS:85124486407
SN - 0045-2068
VL - 121
JO - Bioorganic Chemistry
JF - Bioorganic Chemistry
M1 - 105660
ER -
