The First Convergent Synthesis of 23,23-Difluoro-25-hydroxyvitamin D3 and Its 24-Hydroxy Derivatives: Preliminary Assessment of Biological Activities

In this paper, we report an efficient synthetic route for the 23,23-difluoro-25-hydroxyvitamin D3 (5) and its 24-hydroxylated analogues (7,8), which are candidates for the CYP24A1 main metabolites of 5. The key fragments, 23,23-difluoro-CD-ring precursors (9–11), were synthesized starting from Inhof...

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Bibliographic Details
Published in:Molecules (Basel, Switzerland) Switzerland), 2022-08, Vol.27 (16), p.5352
Main Authors: Mototani, Sayuri, Kawagoe, Fumihiro, Yasuda, Kaori, Mano, Hiroki, Sakaki, Toshiyuki, Kittaka, Atsushi
Format: Article
Language:English
Subjects:
23,23-difluorovitamin D3 analogues
Alcohol
Chromatography
Crystallography
CYP24A1
DAST
Metabolism
Metabolites
Reagents
Sterols
synthesis
VDR
vitamin D3 metabolite
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Summary:In this paper, we report an efficient synthetic route for the 23,23-difluoro-25-hydroxyvitamin D3 (5) and its 24-hydroxylated analogues (7,8), which are candidates for the CYP24A1 main metabolites of 5. The key fragments, 23,23-difluoro-CD-ring precursors (9–11), were synthesized starting from Inhoffen-Lythgoe diol (12), and introduction of the C23 difluoro unit to α-ketoester (19) was achieved using N,N-diethylaminosulfur trifluoride (DAST). Preliminary biological evaluation revealed that 23,23-F2-25(OH)D3 (5) showed approximately eight times higher resistance to CYP24A1 metabolism and 12 times lower VDR-binding affinity than its nonfluorinated counterpart 25(OH)D3 (1).
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules27165352