scholarly journals Strategies for the Synthesis of 19-nor-Vitamin D Analogs

2020 ◽  
Vol 13 (8) ◽  
pp. 159
Author(s):  
Susana Fernández ◽  
Miguel Ferrero
Keyword(s):  
Vitamin D ◽  
Active Form ◽  
Cell Types ◽  
Malignant Cells ◽  
Phosphate Homeostasis ◽  
Dihydroxyvitamin D3 ◽  
Antiproliferative Effects ◽  
The Past ◽  
Natural Hormone ◽  
Stimulation Of

1α,25-Dihydroxyvitamin D3 [1α,25-(OH)2-D3], the hormonally active form of vitamin D3, classically regulates bone formation, calcium, and phosphate homeostasis. In addition, this hormone also exerts non-classical effects in a wide variety of target tissues and cell types, such as inhibition of the proliferation and stimulation of the differentiation of normal and malignant cells. However, to produce these actions, supraphysiological doses are required resulting in calcemic effects that limit the use of this natural hormone. During the past 30 years, many structurally modified analogs of the 1α,25-(OH)2-D3 have been synthesized in order to find derivatives that can dissociate the beneficial antiproliferative effects from undesired calcemic effects. Among these candidates, 1α,25-(OH)2-19-nor-D3 analogs have shown promise as good derivatives since they show equal or better activity relative to the parent hormone but with reduced calcemic effects. In this review, we describe the synthetic strategies to obtain the 19-nor-D3 derivatives and briefly describe their physiological activities.

Mechanisms implicated in the growth regulatory effects of vitamin D in breast cancer.

2002 ◽  
pp. 45-59 ◽  
Author(s):  
K W Colston ◽  
C M√∏rk Hansen
Keyword(s):  
Breast Cancer ◽  
Vitamin D ◽  
Bone Mineralization ◽  
Active Form ◽  
Cell Types ◽  
Cell Cycle Regulators ◽  
Dihydroxyvitamin D ◽  
Cell Growth And Differentiation ◽  
Regulatory Effects ◽  
Apoptotic Effects

It is now well established that, in addition to its central role in the maintenance of extracellular calcium levels and bone mineralization, 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), the active form of vitamin D, also acts as a modulator of cell growth and differentiation in a number of cell types, including breast cancer cells. The anti-proliferative effects of 1,25(OH)(2)D(3) have been linked to suppression of growth stimulatory signals and potentiation of growth inhibitory signals, which lead to changes in cell cycle regulators such as p21(WAF-1/CIP1) and p27(kip1), cyclins and retinoblastoma protein as well as induction of apoptosis. Such studies have led to interest in the potential use of 1,25(OH)(2)D(3) in the treatment or prevention of certain cancers. Since this approach is limited by the tendency of 1,25(OH)(2)D(3) to cause hypercalcaemia, synthetic vitamin D analogues have been developed which display separation of the growth regulating effects from calcium mobilizing actions. This review examines mechanisms by which 1,25(OH)(2)D(3) and its active analogues exert both anti-proliferative and pro-apoptotic effects and describes some of the synthetic analogues that have been shown to be of particular interest in relation to breast cancer.

Vitamin D3 and glucose-6-phosphate dehydrogenase in rat duodenal epithelial cells

1989 ◽  
Vol 257 (5) ◽  
pp. G760-G765
Author(s):  
L. B. Nasr ◽  
J. D. Monet ◽  
P. Lucas ◽  
C. A. Bader
Keyword(s):  
Vitamin D ◽  
Intraperitoneal Administration ◽  
Middle Part ◽  
G6pd Activity ◽  
Dihydroxyvitamin D3 ◽  
Rat Duodenum ◽  
High Level ◽  
Glucose 6 Phosphate Dehydrogenase ◽  
Stimulation Of

A microdensitometric method was employed to determine enzyme activities in situ in undisrupted tissue rat duodenum. The effect of 1 alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3] on glucose-6-phosphate dehydrogenase (G6PD) activity and on the two utilization pathways of synthesized NADPH, H1 (mixed function oxidation) and H2 (biosynthesis), was studied. In normal animals, a crypt-to-villus gradient of G6PD activity and of both NADPH utilization pathways was observed. A high level of NADPH utilization occurred predominantly via the H2 pathway. In vitamin D-deficient rat animals, G6PD activity in the middle part of the villus was approximately 60% lower than in normal animals [10.05 +/- 0.35 vs. 3.95 +/- 0.26 (means +/- SE) A585.min-1.micron-3 X 10(5), P less than 0.001] with reduced NADPH utilization via the H2 pathway (8.39 +/- 0.49 vs. 2.73 +/- 0.43 A585.min-1.micron-3 X 10(5), P less than 0.001) but not the H1 pathway (1.65 +/- 0.17 vs. 1.22 +/- 0.19 A585.min-1.micron-3 X 10(5), P = NS). Intraperitoneal administration of 1,25(OH)2D3 (500 pmol) to vitamin D-deficient animals resulted in increased G6PD activity within 30 min (4.09 +/- 0.38 vs. 5.51 +/- 0.39 A585.min-1.micron-3 X 10(5), P less than 0.05), attaining normal levels within 2 h. The H2 but not the H1 pathway of NADPH utilization increased significantly in response to 1,25(OH)2D3. This increase is essentially located in the basal and middle parts of the villus. Thus 1,25(OH)2D3 may influence biosynthesis in the duodenum via stimulation of G6PD activity and the H2 pathway of NADPH utilization.

Stimulation of 24R,25-dihydroxyvitamin D3 synthesis by metabolites of vitamin D3

1983 ◽  
Vol 245 (4) ◽  
pp. E359-E364 ◽  
Author(s):  
G. S. Reddy ◽  
G. Jones ◽  
S. W. Kooh ◽  
D. Fraser ◽  
H. F. DeLuca
Keyword(s):  
Vitamin D ◽  
Vitamin D3 ◽  
The Other ◽  
Hydroxyl Group ◽  
Vitamin D Metabolites ◽  
Structural Requirements ◽  
Dihydroxyvitamin D3 ◽  
Hydroxylated Metabolites ◽  
Perfusion Period ◽  
Stimulation Of

Previously we have shown that the isolated perfused kidney from vitamin D-deficient rats converts [3H]25(OH)D3 into [3H]1 alpha,25(OH)2D3. When certain vitamin D metabolites were added to perfusate the same kidney began to synthesize [3H]24R,25(OH)2D3. In this study we investigated the structural requirements of the vitamin D molecule necessary to stimulate synthesis of [3H]24R,25(OH)2D3 in a 1-hydroxylating kidney. Kidneys were perfused with tracer [3H]25(OH)D3 (450 pM) alone and in the presence of a variety of hydroxylated metabolites and fluorinated analogues of vitamin D3 at concentrations of 450 pM to 25 microM. Tracer [3H]25(OH)D3 alone resulted in synthesis of only [3H]1 alpha,25(OH)2D3 during the 6-h perfusion period. 25-Hydroxylated metabolites [25(OH)D3, 25 nM; 1 alpha,25(OH)2D3, 25 nM; 24R,25(OH)2D3, 25 nM; 24(F)2,25(OH)D3, 50 nM] stimulated [3H]24R,25(OH)2D3 production at 2 h of perfusion. On the other hand, analogues without the 25-hydroxyl group [D3; 1 alpha(OH)D3; 25(F)D3; 1 alpha(OH),25(F)D3; 1 alpha(F)D3; 1 beta(F)D3]; did not stimulate [3H]24R,25(OH)2D3 synthesis. We conclude that the 25-hydroxyl group is an essential determinant of 24-hydroxylation.

scholarly journals Vitamin D Effects on Cell Differentiation and Stemness in Cancer

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2413 ◽  
Author(s):  
Asunción Fernández-Barral ◽  
Pilar Bustamante-Madrid ◽  
Gemma Ferrer-Mayorga ◽  
Antonio Barbáchano ◽  
María Jesús Larriba ◽  
...  
Keyword(s):  
Vitamin D ◽  
Epithelial Mesenchymal Transition ◽  
Current Knowledge ◽  
Cell Types ◽  
Carcinoma Cells ◽  
Dihydroxyvitamin D3 ◽  
Human Carcinoma ◽  
Mesenchymal Transition ◽  
Major Mechanism ◽  
Egf Signaling

Vitamin D3 is the precursor of 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3), a pleiotropic hormone that is a major regulator of the human genome. 1,25(OH)2D3 modulates the phenotype and physiology of many cell types by controlling the expression of hundreds of genes in a tissue- and cell-specific fashion. Vitamin D deficiency is common among cancer patients and numerous studies have reported that 1,25(OH)2D3 promotes the differentiation of a wide panel of cultured carcinoma cells, frequently associated with a reduction in cell proliferation and survival. A major mechanism of this action is inhibition of the epithelial–mesenchymal transition, which in turn is largely based on antagonism of the Wnt/β-catenin, TGF-β and EGF signaling pathways. In addition, 1,25(OH)2D3 controls the gene expression profile and phenotype of cancer-associated fibroblasts (CAFs), which are important players in the tumorigenic process. Moreover, recent data suggest a regulatory role of 1,25(OH)2D3 in the biology of normal and cancer stem cells (CSCs). Here, we revise the current knowledge of the molecular and genetic basis of the regulation by 1,25(OH)2D3 of the differentiation and stemness of human carcinoma cells, CAFs and CSCs. These effects support a homeostatic non-cytotoxic anticancer action of 1,25(OH)2D3 based on reprogramming of the phenotype of several cell types.

scholarly journals Is the Vitamin D Receptor Found in Muscle?

Endocrinology ◽  
2010 ◽  
Vol 152 (2) ◽  
pp. 354-363 ◽  
Author(s):  
Yongji Wang ◽  
Hector F. DeLuca
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Bone Mineralization ◽  
Active Form ◽  
Dihydroxyvitamin D3 ◽  
Neuromuscular Activity ◽  
Immunohistochemical Assay ◽  
Underlying Mechanisms ◽  
Positive Results ◽  
Phosphorus Levels

Abstract The active form of vitamin D, 1α,25-dihydroxyvitamin D3, is critical for the regulation of serum calcium and phosphorus levels that in turn support bone mineralization and neuromuscular activity. It is well known that vitamin D deficiency causes rachitic/osteomalacic myopathy and cardiac disorder and the provision of vitamin D can reverse the symptoms. However, the underlying mechanisms remain unclear. The question of whether the vitamin D receptor is found in muscle has been debated but not settled. We recently studied all available antibodies against the vitamin D receptor and found that most antibodies used detect proteins other than the vitamin D receptor, and therefore, the utility of these antibodies may generate the false-positive results. Using antibodies that do not detect proteins in tissues from vitamin D receptor null mice, we have developed a specific and sensitive immunohistochemical assay. The results from this investigation show that the vitamin D receptor is undetectable in skeletal, cardiac, and smooth muscle, suggesting that the function of vitamin D on muscle is either of an indirect nature or does not involve the known receptor.

Altered regulation of cytosolic Ca2+ concentration in dendritic cells from klotho hypomorphic mice

2013 ◽  
Vol 305 (1) ◽  
pp. C70-C77 ◽  
Author(s):  
Ekaterina Shumilina ◽  
Meerim K. Nurbaeva ◽  
Wenting Yang ◽  
Evi Schmid ◽  
Kalina Szteyn ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Vitamin D ◽  
Dendritic Cells ◽  
Active Form ◽  
Biologically Active ◽  
Deficient Diet ◽  
Dihydroxyvitamin D3 ◽  
Mhc Ii ◽  
Macrophage Colony ◽  
Antigen Presenting

The function of dendritic cells (DCs), antigen-presenting cells regulating naïve T-cells, is regulated by cytosolic Ca2+ concentration ([Ca2+]i). [Ca2+]i is increased by store-operated Ca2+ entry and decreased by K+-independent (NCX) and K+-dependent (NCKX) Na+/Ca2+ exchangers. NCKX exchangers are stimulated by immunosuppressive 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the biologically active form of vitamin D. Formation of 1,25(OH)2D3 is inhibited by the antiaging protein Klotho. Thus 1,25(OH)2D3 plasma levels are excessive in Klotho-deficient mice ( klotho hm). The present study explored whether Klotho deficiency modifies [Ca2+]i regulation in DCs. DCs were isolated from the bone marrow of klotho hm mice and wild-type mice ( klotho+/+) and cultured for 7–9 days with granulocyte-macrophage colony-stimulating factor. According to major histocompatibility complex II (MHC II) and CD86 expression, differentiation and lipopolysaccharide (LPS)-induced maturation were similar in klotho hm DCs and klotho+/+ DCs. However, NCKX1 membrane abundance and NCX/NCKX-activity were significantly enhanced in klotho hm DCs. The [Ca2+]i increase upon acute application of LPS (1 μg/ml) was significantly lower in klotho hm DCs than in klotho+/+ DCs, a difference reversed by the NCKX blocker 3′,4′-dichlorobenzamyl (DBZ; 10 μM). CCL21-dependent migration was significantly less in klotho hm DCs than in klotho+/+ DCs but could be restored by DBZ. NCKX activity was enhanced by pretreatment of klotho+/+ DC precursors with 1,25(OH)2D3 the first 2 days after isolation from bone marrow. Feeding klotho hm mice a vitamin D-deficient diet decreased NCKX activity, augmented LPS-induced increase of [Ca2+]i, and enhanced migration of klotho hm DCs, thus dissipating the differences between klotho hm DCs and klotho+/+ DCs. In conclusion, Klotho deficiency upregulates NCKX1 membrane abundance and Na+/Ca2+-exchange activity, thus blunting the increase of [Ca2+]i following LPS exposure and CCL21-mediated migration. The effects are in large part due to excessive 1,25(OH)2D3 formation.

Insulin modulates the stimulation of renal 1,25-dihydroxyvitamin D3 production by parathyroid hormone

1985 ◽  
Vol 109 (2) ◽  
pp. 243-248 ◽  
Author(s):  
Nirandon Wongsurawat ◽  
H. James Armbrecht
Keyword(s):  
Vitamin D ◽  
Parathyroid Hormone ◽  
Diabetic Rats ◽  
Biologically Active ◽  
Renal Handling ◽  
Dihydroxyvitamin D3 ◽  
Dihydroxyvitamin D ◽  
Maximal Stimulation ◽  
Insulin Replacement ◽  
Stimulation Of

Abstract. Previous studies have shown that there is an impairment in renal production of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), the major biologically active metabolite of vitamin D3, in diabetes. This impairment is not due to a deficiency in the parathyroid hormone (PTH), a major stimulator of renal 1,25(OH)2D3 production. Therefore, we have investigated the capacity of PTH to stimulate 1,25(OH)2D3 production in insulin deficiency and with insulin replacement. Experiments were performed in rats fed a 0.6% calcium, vitamin D sufficient diet for 2 weeks. Thyroparathyroidectomy was performed on all rats. Rats to be rendered diabetic were injected with streptozotocin immediately after surgery. In non-diabetic rats, PTH administration significantly increased renal 1,25(OH)2D3 production (11 ± 2 vs 46 ± 5 pg/min/g; P < 0.05). In diabetic rats, however, PTH caused only a modest increase in 1,25(OH)2D3 production (11 ± 1 vs 19 ± 4 pg/min/g; P < 0.05). With insulin replacement, PTH stimulation of 1,25(OH)2D3 production was markedly increased over that seen in diabetic rats (48 ± 12 vs 19 ± 4 pg/min/g; P < 0.05). PTH was equally effective in raising serum calcium, depressing serum phosphorus and tubular reabsorption of phosphate in non-diabetic as well as in diabetic rats. These results demonstrate that insulin is necessary for the maximal stimulation of renal 1,25(OH)2D3 production by PTH. However, insulin is not necessary for PTH action in terms of renal handling of phosphate and inducing hypercalcaemia. These results suggest multiple pathways for the action of PTH, only some of which are insulin requiring.

scholarly journals Lithocholic Acid Amides as Potent Vitamin D Receptor Agonists

Biomolecules ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 130
Author(s):  
Ayana Yoshihara ◽  
Haru Kawasaki ◽  
Hiroyuki Masuno ◽  
Koki Takada ◽  
Nobutaka Numoto ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Lithocholic Acid ◽  
Active Form ◽  
Binding Pocket ◽  
Carboxyl Group ◽  
Amino Acid Residues ◽  
Dihydroxyvitamin D3 ◽  
Biological Phenomena ◽  
Amide Derivatives

1α,25-Dihydroxyvitamin D3 [1α,25(OH)2D3, 1] is an active form of vitamin D3 and regulates various biological phenomena, including calcium and phosphate homeostasis, bone metabolism, and immune response via binding to and activation of vitamin D receptor (VDR). Lithocholic acid (LCA, 2) was identified as a second endogenous agonist of VDR, though its potency is very low. However, the lithocholic acid derivative 3 (Dcha-20) is a more potent agonist than 1α,25(OH)2D3, (1), and its carboxyl group has similar interactions to the 1,3-dihydroxyl groups of 1 with amino acid residues in the VDR ligand-binding pocket. Here, we designed and synthesized amide derivatives of 3 in order to clarify the role of the carboxyl group. The synthesized amide derivatives showed HL-60 cell differentiation-inducing activity with potency that depended upon the substituent on the amide nitrogen atom. Among them, the N-cyanoamide 6 is more active than either 1 or 3.

scholarly journals Impact of Epigenetics on Complications of Fanconi Anemia: The Role of Vitamin D-Modulated Immunity

Nutrients ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1355
Author(s):  
Eunike Velleuer ◽  
Carsten Carlberg
Keyword(s):  
Vitamin D ◽  
Fanconi Anemia ◽  
Bone Marrow Failure ◽  
Active Form ◽  
Cellular Growth ◽  
Biologically Active ◽  
Fine Tuning ◽  
Dihydroxyvitamin D3 ◽  
Increased Risk ◽  
The Individual

Fanconi anemia (FA) is a rare disorder with the clinical characteristics of (i) specific malformations at birth, (ii) progressive bone marrow failure already during early childhood and (iii) dramatically increased risk of developing cancer in early age, such as acute myeloid leukemia and squamous cell carcinoma. Patients with FA show DNA fragility due to a defect in the DNA repair machinery based on predominately recessive mutations in 23 genes. Interestingly, patients originating from the same family and sharing an identical mutation, frequently show significant differences in their clinical presentation. This implies that epigenetics plays an important role in the manifestation of the disease. The biologically active form of vitamin D, 1α,25-dihydroxyvitamin D3 controls cellular growth, differentiation and apoptosis via the modulation of the immune system. The nuclear hormone activates the transcription factor vitamin D receptor that affects, via fine-tuning of the epigenome, the transcription of >1000 human genes. In this review, we discuss that changes in the epigenome, in particular in immune cells, may be central for the clinical manifestation of FA. These epigenetic changes can be modulated by vitamin D suggesting that the individual FA patient’s vitamin D status and responsiveness are of critical importance for disease progression.

scholarly journals Calmodulin-Dependent Kinase IV Stimulates Vitamin D Receptor-Mediated Transcription

2005 ◽  
Vol 19 (9) ◽  
pp. 2309-2319 ◽  
Author(s):  
Tara I. Ellison ◽  
Diane R. Dowd ◽  
Paul N. MacDonald
Keyword(s):  
Gene Expression ◽  
Vitamin D ◽  
Reporter Gene ◽  
Vitamin D Receptor ◽  
Active Form ◽  
Metabolic Labeling ◽  
Dihydroxyvitamin D3 ◽  
Steroid Receptor Coactivator ◽  
Functional Consequences ◽  
Dependent Interaction

Abstract 1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] promotes intestinal absorption of calcium primarily by binding to the vitamin D receptor (VDR) and regulating gene expression. 1,25-(OH)2D3 also exerts rapid actions at the cell membrane that include increasing intracellular calcium levels and activating protein kinase cascades. To explore potential cross talk between calcium signaling elicited by the nongenomic actions of 1,25-(OH)2D3 and the genomic pathway mediated by VDR, we examined the effects of activated Ca2+/calmodulin-dependent kinases (CaMKs) on 1,25-(OH)2D3/VDR-mediated transcription. Expression of a constitutively active form of CaMKIV dramatically stimulated 1,25-(OH)2D3-activated reporter gene expression in COS-7, HeLa, and ROS17/2.8 cell lines. Metabolic labeling studies indicated that CaMKIV increased VDR phosphorylation levels. In addition, CaMKIV increased the independent transcription activity of the VDR coactivator SRC (steroid receptor coactivator) 1, and promoted ligand-dependent interaction between VDR and SRC coactivator proteins in mammalian two-hybrid studies. The functional consequences of this multifaceted mechanism of CaMKIV action were revealed by reporter gene studies, which showed that CaMKIV and select SRC coactivators synergistically enhanced VDR-mediated transcription. These studies support a model in which CaMKIV signaling stimulates VDR-mediated transcription by increasing phosphorylation levels of VDR and enhancing autonomous SRC activity, resulting in higher 1,25-(OH)2D3-dependent interaction between VDR and SRC coactivators.

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