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

Pawel Brzeminski; Adrian Fabisiak; Radomir M Slominski; Tae-Kang Kim; Zorica Janjetovic; Ewa Podgorska; Yuwei Song; Mohammad Saleem; Sivani B Reddy; Shariq Qayyum; Yuhua Song; Robert C Tuckey; Venkatram Atigadda; Anton M Jetten; Rafal R Sicinski; Chander Raman; Andrzej T Slominski

doi:10.1016/j.bioorg.2022.105660

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

Bioorg Chem. 2022 Apr:121:105660. doi: 10.1016/j.bioorg.2022.105660. Epub 2022 Feb 8.

Authors

Pawel Brzeminski¹, Adrian Fabisiak¹, Radomir M Slominski², Tae-Kang Kim³, Zorica Janjetovic³, Ewa Podgorska³, Yuwei Song², Mohammad Saleem³, Sivani B Reddy³, Shariq Qayyum³, Yuhua Song⁴, Robert C Tuckey⁵, Venkatram Atigadda³, Anton M Jetten⁶, Rafal R Sicinski⁷, Chander Raman³, Andrzej T Slominski⁸

Affiliations

¹ Department of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland; Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
² Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Graduate Biomedical Sciences Program, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
³ Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
⁴ Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
⁵ School of Molecular Sciences, The University of Western Australia, Perth, WA, Australia.
⁶ Cell Biology Section, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
⁷ Department of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland.
⁸ Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Pathology Laboratory Service, Veteran Administration Medical Center at Birmingham, Birmingham, AL 35294, USA. Electronic address: aslominski@uabmc.edu.

Abstract

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.

Keywords: Active forms of vitamin D; Biological activity; Keratinocytes; Receptors for vitamin D; Vitamin D.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Cholesterol Side-Chain Cleavage Enzyme* / metabolism
Humans
Receptors, Calcitriol / metabolism
Receptors, Cytoplasmic and Nuclear
Vitamin D / metabolism
Vitamins*

Substances

Receptors, Calcitriol
Receptors, Cytoplasmic and Nuclear
Vitamins
Vitamin D
Cholesterol Side-Chain Cleavage Enzyme

Abstract

Publication types

MeSH terms

Substances

Grants and funding