Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Stereoselective Synthesis of 24-Fluoro-25-Hydroxyvitamin D3 Analogues and Their Stability to hCYP24A1-Dependent Catabolism.

ABSTRACT: Two 24-fluoro-25-hydroxyvitamin D3 analogues (3,4) were synthesized in a convergent manner. The introduction of a stereocenter to the vitamin D3 side-chain C24 position was achieved via Sharpless dihydroxylation, and a deoxyfluorination reaction was utilized for the fluorination step. Comparison between (24R)- and (24S)-24-fluoro-25-hydroxyvitamin D3 revealed that the C24-R-configuration isomer 4 was more resistant to CYP24A1-dependent metabolism than its 24S-isomer 3. The new synthetic route of the CYP24A1 main metabolite (24R)-24,25-dihydroxyvitamin D3 (6) and its 24S-isomer (5) was also studied using synthetic intermediates (30,31) in parallel.

SUBMITTER: Kawagoe F

PROVIDER: S-EPMC8584271 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Stereoselective Synthesis of 24-Fluoro-25-Hydroxyvitamin D3 Analogues and Their Stability to hCYP24A1-Dependent Catabolism.

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

International journal of molecular sciences 20211101 21

Two 24-fluoro-25-hydroxyvitamin D3 analogues (3,4) were synthesized in a convergent manner. The introduction of a stereocenter to the vitamin D3 side-chain C24 position was achieved via Sharpless dihydroxylation, and a deoxyfluorination reaction was utilized for the fluorination step. Comparison between (24R)- and (24S)-24-fluoro-25-hydroxyvitamin D3 revealed that the C24-R-configuration isomer 4 was more resistant to CYP ...[more]

PMID: 34769295

Similar Datasets

Gene-regulatory potential of 25-hydroxyvitamin D3 and D2

Project description:In this study, we compared the modulation of the transcriptome of human PBMCs by the vitamin D metabolites 25-hydroxyvitamin D3 (25(OH)D3), 25(OH)D2 and 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3).

2022-06-21 | GSE199273 | GEO

Quantitative NMR (qNMR) spectroscopy based investigation of the absolute content, stability and isomerization of 25-hydroxyvitamin D2/D3 and 24(R),25-dihydroxyvitamin D2 in solution phase.

Project description:Vitamin D is an important parameter, in serum/plasma based diagnostic analysis, for the determination of optimal regulation of calcium and phosphate homeostases in the human body, vital for the monitoring/progression of osteomalacia and rickets. Particularly, the quantification of 25-hydroxyvitamin D2, 25-hydroxyvitamin D3 and 24R,25-dihydroxyvitamin D in blood is an excellent indicator for the vitamin D status of a patient. For this purpose, LC-MS/MS methods, based on appropriate vitamin D reference standards, are considered to be 'gold standard' for such measurements. We have utilized quantitative NMR spectroscopy to determine the absolute content of these molecules, available as non-certified chemicals, and have determined the stability of these callibrators in borderline polar solvents at room temperature. We have observed significant isomerization of the analytes, which can play a big role in quantification of these analytes by hyphenated LC and GC analytical techniques. Appropriate explanations are given for the observation of new impurities with time in solution phase. The spin system selected for quantitation was determined using relevant 1D and 2D NMR pulse sequences. The advantage of the qNMR approach is that it is based on the quantification of atoms rather than molecular properties (e.g., quantitation by LC/UV, GC, etc.). Since the signals in an NMR spectrum are different nuclear spin-systems dispersed precisely in a magnetic environment, with the intensity being directly proportional to the amount of a particular type of nuclear spin, this technique delivers unparalleled information about the chemical structure and the absolute content.

| S-EPMC8863798 | biostudies-literature

Identification of a vitamin D-response element in the rat calcidiol (25-hydroxyvitamin D3) 24-hydroxylase gene.

Project description:The calcidiol (25-hydroxyvitamin D3) 24-hydroxylase is one of the key enzymes in the metabolism of vitamin D. This enzyme acts on both calcidiol and calcitriol (1,25-dihydroxyvitamin D3) to initiate degradation of these potent vitamin D metabolites and is tightly regulated. Calcitriol itself induces this enzyme and acts at the transcriptional level. Transcriptional regulation of genes by calcitriol has been shown to occur via the vitamin D-receptor binding to a vitamin D-response element located upstream of the transcription start site. We now report a vitamin D-response element located between nt -262 and nt -238 of the rat calcidiol 24-hydroxylase gene. This sequence binds the calcitriol receptor and confers vitamin D-dependent transactivation of transcription to its own, as well as heterologous, promoter.

| S-EPMC521420 | biostudies-other

Serum 25-Hydroxyvitamin D3 and Mammography Density among Mexican Women.

Project description:Low circulating levels of vitamin D and high mammographic density (MD) have been associated with higher risk of breast cancer. Although some evidence suggested an inverse association between circulating vitamin D and MD, no studies have investigated this association among Mexican women. We examined whether serum 25-hydroxyvitamin D3 [25(OH)D3] levels were associated with MD in a cross-sectional study nested within the large Mexican Teacher's Cohort. This study included 491 premenopausal women with a mean age of 42.9 years. Serum 25(OH)D3 levels were measured by liquid chromatography/tandem mass spectrometry. Linear regression and non-linear adjusted models were used to estimate the association of MD with serum 25(OH)D3. Median serum 25(OH)D3 level was 27.3 (23.3-32.8) (ng/ml). Forty one (8%) women had 25(OH)D3 levels in the deficient range (< 20 ng/ml). Body mass index (BMI) and total physical activity were significantly correlated with 25(OH)D3 (r = -0.109, P = 0.019 and r = 0.095, P = 0.003, respectively). In the multivariable linear regression, no significant association was observed between 25(OH)D3 levels and MD overall. However, in stratified analyses, higher serum 25(OH)D3 levels (≥27.3 ng/ml) were significantly inversely associated with percent MD among women with BMI below the median (β = -0.52, P = 0.047). Although no significant association was observed between serum 25(OH)D3 and percent MD in the overall population, specific subgroups of women may benefit from higher serum 25(OH)D3 levels.

| S-EPMC5001725 | biostudies-literature

Solubilization and reconstitution of kidney 25-hydroxyvitamin D3 1 alpha- and 24-hydroxylases from vitamin D-replete pigs.

Project description:Pig kidney mitochondrial 25-hydroxyvitamin D3 1 alpha- and 24-hydroxylase activities have been solubilized with cholate/Emulgen 911 and reconstituted with NADPH, ferredoxin reductase and ferredoxin. All three of these components are required for full catalytic activity of both enzymes. Both products were identified by co-chromatography with authentic metabolites on both normal and reverse-phase h.p.l.c. using solvent systems which were shown to separate 10-oxo-19-nor-25-hydroxyvitamin D3 from 1,25-dihydroxyvitamin D3 [1,25-(OH)2-D3]. In addition, periodate treatment of the 24,25-(OH)2-D3 product resulted in complete loss of the product as measured by protein-binding assay. Further purification by p-chloroamphetamine-Sepharose chromatography of a solubilized extract from a pig fed a normal diet increased the specific content of the cytochrome P-450 from 0.019 to 0.239 nmol/mg and the 1 alpha-hydroxylase activity from 4.75 to 268 pmol/h per mg. Activity of the 24-hydroxylase in the crude solubilized extract was 6.3 pmol/h per mg, but was undetectable after partial purification by a p-chloroamphetamine-Sepharose column. However, further fractionation of this material by DEAE-Sepharose chromatography resulted in a further increase in 1 alpha-hydroxylase activity to 430 pmol/h per mg and detection of 24-hydroxylase in a separate fraction at a level of 53 pmol/h per mg. Production of 1,25-(OH)2-D3 was linear with time up to 2 h and was dependent upon ferredoxin concentration as well as cytochrome P-450 concentration in the range of 0-40 nM. In the presence of excess ferredoxin and adequate amounts of cytochrome P-450, 1,25-(OH)2-D3 production was also dependent upon substrate concentrations in the range of 0.25 to 2.5 microM yielding an estimated Km of 1 microM. In the presence of excess substrate and ferredoxin, the catalytic-centre activity of the enzyme was estimated to be 1 h-1.

| S-EPMC1138545 | biostudies-other

Differential Effects of 25-Hydroxyvitamin D3 versus 1α 25-Dihydroxyvitamin D3 on Adipose Tissue Browning in CKD-Associated Cachexia.

Project description:Patients with chronic kidney disease (CKD) often have low serum concentrations of 25(OH)D3 and 1,25(OH)2D3. We investigated the differential effects of 25(OH)D3 versus 1,25(OH)2D3 repletion in mice with surgically induced CKD. Intraperitoneal supplementation of 25(OH)D3 (75 μg/kg/day) or 1,25(OH)2D3 (60 ng/kg/day) for 6 weeks normalized serum 25(OH)D3 or 1,25(OH)2D3 concentrations in CKD mice, respectively. Repletion of 25(OH)D3 normalized appetite, significantly improved weight gain, increased fat and lean mass content and in vivo muscle function, as well as attenuated elevated resting metabolic rate relative to repletion of 1,25(OH)2D3 in CKD mice. Repletion of 25(OH)D3 in CKD mice attenuated adipose tissue browning as well as ameliorated perturbations of energy homeostasis in adipose tissue and skeletal muscle, whereas repletion of 1,25(OH)2D3 did not. Significant improvement of muscle fiber size and normalization of fat infiltration of gastrocnemius was apparent with repletion of 25(OH)D3 but not with 1,25(OH)2D3 in CKD mice. This was accompanied by attenuation of the aberrant gene expression of muscle mass regulatory signaling, molecular pathways related to muscle fibrosis as well as muscle expression profile associated with skeletal muscle wasting in CKD mice. Our findings provide evidence that repletion of 25(OH)D3 exerts metabolic advantages over repletion of 1,25(OH)2D3 by attenuating adipose tissue browning and muscle wasting in CKD mice.

| S-EPMC8699879 | biostudies-literature

Circulating 25-hydroxyvitamin D3 and survival after diagnosis with kidney cancer.

Project description:Prospective cohort studies have provided some evidence that circulating vitamin D is associated with risk of, and survival from, renal cell carcinoma (RCC), but it is unclear whether concentrations of vitamin D at the time of diagnosis of RCC are associated with prognosis. We conducted a case-cohort study of 630 RCC cases, including 203 deaths, from a multicenter case-control study in Eastern Europe. Vitamin D was assessed as 25-hydroxyvitamin D3 [25(OH)D3], and we used weighted Cox models to estimate hazard ratios (HR) and 95% confidence intervals (CI) by categories of season-adjusted 25(OH)D3. Higher concentrations of 25(OH)D3 were associated with lower risk of death after adjusting for stage, age, sex, and country (HR highest vs. lowest category 0.57; 95% CI, 0.34-0.97). The inverse associations of 25(OH)D3 with death were most notable among those who died from non-RCC causes and those diagnosed with early-stage disease. In summary, 25(OH)D3 concentration at diagnosis of RCC was inversely associated with all-cause mortality rates, but not specifically with RCC outcome.

| S-EPMC4526455 | biostudies-literature

Cloning and expression of rat 25-hydroxyvitamin D3-1alpha-hydroxylase cDNA.

Project description:A full-length cDNA for the rat kidney mitochondrial cytochrome P450 mixed function oxidase, 25-hydroxyvitamin D3-1alpha-hydroxylase (P4501alpha), was cloned from a vitamin D-deficient rat kidney cDNA library and subcloned into the mammalian expression vector pcDNA 3.1(+). When P4501alpha cDNA was transfected into COS-7 transformed monkey kidney cells, they expressed 25-hydroxyvitamin D3-1alpha-hydroxylase activity. The sequence analysis showed that P4501alpha was of 2,469 bp long and contained an ORF encoding 501 amino acids. The deduced amino acid sequence showed a 53% similarity and 44% identity to the vitamin D3-25-hydroxylase (CYP27), whereas it has 42.6% similarity and 34% identity with the 25-hydroxyvitamin D3-24-hydroxylase (CYP24). Thus, it composes a new subfamily of the CYP27 family. Further, it is more closely related to the CYP27 than to the CYP24. The expression of P4501alpha mRNA was greatly increased in the kidney of vitamin D-deficient rats. In rats with the enhanced renal production of 1alpha,25-dihydroxyvitamin D3 (rats fed a low Ca diet), P4501alpha mRNA was greatly increased in the renal proximal convoluted tubules.

| S-EPMC24239 | biostudies-literature

Regulation of Mycobacterium-specific mononuclear cell responses by 25-hydroxyvitamin D3.

Project description:The active vitamin D metabolite, 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), has been shown to be an important regulator of innate and adaptive immune function. In addition, synthesis of 1,25(OH)(2)D(3) from 25-hydroxyvitamin D(3) (25(OH)D(3)) by the enzyme 1?-hydroxylase in monocytes upon activation by TLR signaling has been found to regulate innate immune responses of monocytes in an intracrine fashion. In this study we wanted to determine what cells expressed 1?-hydroxylase in stimulated peripheral blood mononuclear cell (PBMC) cultures and if conversion of 25(OH)D(3) to 1,25(OH)(2)D(3) in PBMC cultures regulated antigen-specific immune responses. Initially, we found that stimulation of PBMCs from animals vaccinated with Mycobacterium bovis (M. bovis) BCG with purified protein derivative of M. bovis (M. bovis PPD) induced 1?-hydroxylase gene expression and that treatment with a physiological concentration of 25(OH)D(3) down-regulated IFN-? and IL-17F gene expression. Next, we stimulated PBMCs from M. bovis BCG-vaccinated and non-vaccinated cattle with M. bovis PPD and sorted them by FACS according to surface markers for monocytes/macrophages (CD14), B cells (IgM), and T cells (CD3). Sorting the PBMCs revealed that 1?-hydroxylase expression was induced in the monocytes and B cells, but not in the T cells. Furthermore, treatment of stimulated PBMCs with 25(OH)D(3) down-regulated antigen-specific IFN-? and IL-17F responses in the T cells, even though 1?-hydroxylase expression was not induced in the T cells. Based on evidence of no T cell 1?-hydroxylase we hypothesize that activated monocytes and B cells synthesize 1,25(OH)(2)D(3) and that 1,25(OH)(2)D(3) down-regulates antigen-specific expression of IFN-? and IL-17F in T cells in a paracrine fashion.

| S-EPMC3125300 | biostudies-literature

Stereoselective synthesis of conjugated fluoro enynes.

Project description:Metalation-electrophilic fluorination of TMS- and TIPS-protected 1,3-benzothiazol-2-yl (BT) propargyl sulfones gave corresponding BT fluoropropargyl sulfones, Julia-Kocienski reagents for the synthesis of fluoro enynes. Both reagents reacted with aldehydes under mild DBU- or LHMDS-mediated conditions, giving high yields of conjugated fluoro enynes with E-stereoselectivity. In comparison to DBU-mediated reactions, stereoselectivity was higher in low-temperature LHMDS-mediated reactions. Two ketones were shown to react as well, using LHMDS as base. In situ removal of the TMS group gave terminal conjugated 2-fluoro 1,3-enynes. Synthetic utility of the fluoro enynes was demonstrated by conversion to internal alkynes and to stereoisomeric fluoro dienes via Sonogashira and Heck couplings.

| S-EPMC3752389 | biostudies-literature