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

ABSTRACT: 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).

SUBMITTER: Mototani S

PROVIDER: S-EPMC9415778 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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

Mototani Sayuri S Kawagoe Fumihiro F Yasuda Kaori K Mano Hiroki H Sakaki Toshiyuki T Kittaka Atsushi A

Molecules (Basel, Switzerland) 20220822 16

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-diethylamin ...[more]

PMID: 36014588

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Project description:Despite differences in the phamacokinetics of 25-hydroxycholecalciferol (25(OH)D3) and 25-hydroxyergocalciferol (25(OH)D2) in man, the effects of these and their 1α-hydroxylated forms (1,25(OH)2D3 and 1,25(OH)2D2) on cellular activity of vitamin D-responsive cells have hardly been compared. We studied differences in the effects of these metabolites on cell number, gene transcription, protein expression and mineralisation of cultured human bone marrow-derived stromal cells (hBMSC) and rapidly mineralising mouse 2T3 osteoblasts. 50-1000 nM 25(OH) and 0.05-10 nM 1,25(OH)2 metabolites were used. At high concentrations, 25(OH)D2/D3 and 1,25(OH)2D2/D3 suppressed cell number in both human and mouse cells. The suppression was greater with cholecalciferol (D3) metabolites than with those of ergocalciferol (D2). In both cell types, 25(OH)D2 and 25(OH)D3 increased the expression of osteopontin, osteocalcin, collagen-1, receptor activator of nuclear factor kappa-B ligand, vitamin D receptor, CYP24A1 and CYP27B1 genes. Whereas there was little or no difference between the effects of 25(OH)D2 and 25(OH)D3 in hBMSCs, differences were observed in the magnitude of the effects of these metabolites on the expression of most studied genes in 2T3 cells. Alkaline phosphatase (ALP) activity was increased by 25(OH)D2/D3 and 1,25(OH)2D2/D3 in hBMSC and 2T3 cells, and the increase was greater with the D3 metabolites at high concentrations. In hBMSCs, mineralisation was also increased by 25(OH)D2/D3 and 1,25(OH)2D2/D3 at high concentrations, with D3 metabolites exerting a greater influence. In 2T3 cells, the effects of these compounds on mineralisation were stimulatory at low concentrations and inhibitory when high concentrations were used. The suppression at high concentrations was greater with the D3 metabolites. These findings suggest that there are differences in the effects of 25-hydroxy and 1α,25(OH)2 metabolites of D3 and D2 on human preosteoblasts and mouse osteoblasts, with the D3 metabolites being more potent in suppressing cell number, increasing ALP activity and influencing mineralisation.

Project description:The physiological relevance C-3 epimer of 25-hydroxyvitamin D (3-epi-25(OH)D) is not well understood among youth. The objective of this study was to assess whether demographic/physiologic characteristics were associated with 3-epi-25(OH)D3 concentrations in youth. Associations between 3-epi-25(OH)D3 and demographics and between 3-epi-25(OH)D3, total 25-hydroxyvitamin (25(OH)D) (25(OH)D2 + 25(OH)D3), total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglycerides were examined in racially/ethnically diverse schoolchildren (n = 682; age, 8-15 years) at Boston-area urban schools. Approximately 50% of participants had detectable 3-epi-25(OH)D3 (range 0.95-3.95 ng/mL). The percentage of 3-epi-25(OH)D3 of total 25(OH)D ranged from 2.5% to 17.0% (median 5.5%). Males were 38% more likely than females to have detectable 3-epi-25(OH)D3 concentrations. Both Asian and black race/ethnicity were associated with lower odds of having detectable 3-epi-25(OH)D3 compared with non-Hispanic white children (Asian vs. white, odds ratio (OR) 0.28, 95% confidence interval (CI) 0.14-0.53; black vs. white, OR 0.38, 95%CI 0.23-0.63, p < 0.001). Having an adequate (20-29 ng/mL) or optimal (>30 ng/mL) 25(OH)D concentration was associated with higher odds of having detectable 3-epi-25(OH)D3 than having an inadequate (<20 ng/mL) concentration (OR 4.78, 95%CI 3.23-6.94 or OR 14.10, 95%CI 7.10-28.0, respectively). There was no association between 3-epi-25(OH)D3 and blood lipids. However, when considering 3-epi-25(OH)D3 as a percentage of total 25(OH)D, total cholesterol was lower in children with percent 3-epi-25(OH)D3 above the median (mean difference -7.1 mg/dL, p = 0.01). In conclusion, among schoolchildren, sex, race/ethnicity, and total serum 25(OH)D concentration is differentially associated with 3-epi-25(OH)D. The physiological relevance of 3-epi-25(OH)D3 may be related to the 3-epi-25(OH)D3 as a percentage of total 25(OH)D and should be considered in future investigations.

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Dataset Information

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

Publications

The First Convergent Synthesis of 23,23-Difluoro-25-hydroxyvitamin D<sub>3</sub> and Its 24-Hydroxy Derivatives: Preliminary Assessment of Biological Activities.

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