The First Convergent Synthesis of 23,23-Difluoro-25-hydroxyvitamin D(3) 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 D(3) (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 Inh...

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Detalles Bibliográficos
Autores principales: Mototani, Sayuri, Kawagoe, Fumihiro, Yasuda, Kaori, Mano, Hiroki, Sakaki, Toshiyuki, Kittaka, Atsushi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9415778/
https://www.ncbi.nlm.nih.gov/pubmed/36014588
http://dx.doi.org/10.3390/molecules27165352
Descripción
Sumario:In this paper, we report an efficient synthetic route for the 23,23-difluoro-25-hydroxyvitamin D(3) (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-F(2)-25(OH)D(3) (5) showed approximately eight times higher resistance to CYP24A1 metabolism and 12 times lower VDR-binding affinity than its nonfluorinated counterpart 25(OH)D(3) (1).

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