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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Autores principales: Mototani, Sayuri, Kawagoe, Fumihiro, Yasuda, Kaori, Mano, Hiroki, Sakaki, Toshiyuki, Kittaka, Atsushi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
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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
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author Mototani, Sayuri
Kawagoe, Fumihiro
Yasuda, Kaori
Mano, Hiroki
Sakaki, Toshiyuki
Kittaka, Atsushi
author_facet Mototani, Sayuri
Kawagoe, Fumihiro
Yasuda, Kaori
Mano, Hiroki
Sakaki, Toshiyuki
Kittaka, Atsushi
author_sort Mototani, Sayuri
collection PubMed
description 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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spelling pubmed-94157782022-08-27 The First Convergent Synthesis of 23,23-Difluoro-25-hydroxyvitamin D(3) and Its 24-Hydroxy Derivatives: Preliminary Assessment of Biological Activities Mototani, Sayuri Kawagoe, Fumihiro Yasuda, Kaori Mano, Hiroki Sakaki, Toshiyuki Kittaka, Atsushi Molecules Article 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). MDPI 2022-08-22 /pmc/articles/PMC9415778/ /pubmed/36014588 http://dx.doi.org/10.3390/molecules27165352 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Mototani, Sayuri
Kawagoe, Fumihiro
Yasuda, Kaori
Mano, Hiroki
Sakaki, Toshiyuki
Kittaka, Atsushi
The First Convergent Synthesis of 23,23-Difluoro-25-hydroxyvitamin D(3) and Its 24-Hydroxy Derivatives: Preliminary Assessment of Biological Activities
title The First Convergent Synthesis of 23,23-Difluoro-25-hydroxyvitamin D(3) and Its 24-Hydroxy Derivatives: Preliminary Assessment of Biological Activities
title_full The First Convergent Synthesis of 23,23-Difluoro-25-hydroxyvitamin D(3) and Its 24-Hydroxy Derivatives: Preliminary Assessment of Biological Activities
title_fullStr The First Convergent Synthesis of 23,23-Difluoro-25-hydroxyvitamin D(3) and Its 24-Hydroxy Derivatives: Preliminary Assessment of Biological Activities
title_full_unstemmed The First Convergent Synthesis of 23,23-Difluoro-25-hydroxyvitamin D(3) and Its 24-Hydroxy Derivatives: Preliminary Assessment of Biological Activities
title_short The First Convergent Synthesis of 23,23-Difluoro-25-hydroxyvitamin D(3) and Its 24-Hydroxy Derivatives: Preliminary Assessment of Biological Activities
title_sort first convergent synthesis of 23,23-difluoro-25-hydroxyvitamin d(3) and its 24-hydroxy derivatives: preliminary assessment of biological activities
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9415778/
https://www.ncbi.nlm.nih.gov/pubmed/36014588
http://dx.doi.org/10.3390/molecules27165352
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