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Vitamin D receptor ligands have potential for the treatment of hyperproliferative diseases and disorders related to the immune system. However, hypercalcemic effects limit their therapeutical uses and call for the development of tissue‐selective new analogs. We have designed and synthesized the first examples of 1α,25‐dihydroxyvitamin D3 analogs bearing an allenic unit attached to the D ring to restrict the side‐chain conformational mobility. The triene system was constructed by a Pd0‐mediated cyclization/Suzuki‐Miyaura cross‐coupling process in the presence of an allenic side chain. The allenic moiety was built through an orthoester‐Claisen rearrangement of a propargylic alcohol. The biological activity and structure of (22S)‐1α,25‐dihydroxy‐17,20‐dien‐24‐homo‐21‐nor‐vitamin D3 bound to binding domain of the vitamin D receptor, provide information concerning side‐chain conformational requirements for biological activity., Looking for side‐chain conformational requirements of vitamin D analogs for selective biological activity, a new active vitamin D analog that has conformationally restricted mobility at the side chain and adopts a similar structure than the natural hormone 1α,25‐dihydroxyvitamin D3 in the binding pocket was designed by docking and synthesized. The highlights of the synthesis include a Pd0‐catalyzed cascade and an orthoester‐Claisen‐rearrangement for the formation of the trienic system and the allenic side‐chain, respectively.

The vitamin D hormone, 1,25dihydroxyvitamin D3 (1,25(OH)2D3), and related compounds derived from vitamin D3 or lumisterol as a result of metabolism via the enzyme CYP11A1, have been shown, when applied 24 hours before or immediately after UV irradiation, to protect human skin cells and skin from DNA damage due to UV exposure, by reducing both cyclobutane pyrimidine dimers (CPD) and oxidative damage in the form of 8‐oxo‐7,8‐dihydro‐2′‐deoxyguanosine (8‐OHdG). We now report that knockdown of either the vitamin D receptor or the endoplasmic reticulum protein ERp57 by small, interfering RNA (siRNA) abolished the reductions in UV‐induced DNA damage with 20‐hydroxyvitamin D3 or 24‐hydroxylumisterol3, as previously shown for 1,25(OH)2D3. Treatment with 1,25(OH)2D3 reduced oxygen consumption rates in UV‐exposed and sham‐exposed human keratinocytes and reduced phosphorylation of cyclic AMP response binding element protein (CREB). Both these actions have been shown to inhibit skin carcinogenesis after chronic UV exposure, consistent with the anticarcinogenic activity of 1,25(OH)2D3. The requirement for a vitamin D receptor for the photoprotective actions of 1,25(OH)2D3 and of naturally occurring CYP11A1‐derived vitamin D–related compounds may explain why mice lacking the vitamin D receptor in skin are more susceptible to UV‐induced skin cancers, whereas mice lacking the 1α‐hydroxylase and thus unable to make 1,25(OH)2D3 are not more susceptible. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Introduction Allergic rhinitis is one of the most common allergic diseases that cause a decrease in quality of life. Over the last decades, the increase in the number of cases is supposed to be a result of industrialization and lifestyle changes. Vitamin D, which is a steroid hormone, has a significant immunomodulatory and antioxidant role in the human body. Objective The objective of the present study is to investigate the role of 1α-25-dihydroxyvitamin D3 levels in allergic rhinitis patients and to compare them to the levels found in the healthy population. Methods A total of 256 participants were included in the present study. Allergic rhinitis is diagnosed with the help of the Allergic Rhinitis and Its Impact on Asthma (ARIA) guidelines confirmed through skin prick tests. Control subjects were selected among people without allergy history, which was also confirmed through skin prick tests. The levels of 1α-25-dihydroxyvitamin D3, immunoglobulin E (IgE), and eosinophil counts were measured in blood samples from both groups. Results The mean value of serum levels of 1α-25-hydroxyvitamin D3 was 25.5 ± 3.74 in the allergic rhinitis group, and 31.58 ± 3.85 in the control subjects. This difference reveals statistically-decreased levels in the allergic rhinitis group (p Conclusion Lower serum levels of 1α-25-hydroxyvitamin D3 were detected in the allergic rhinitis population. This data is also correlated to the IgE response in the study group. A supplement of 1α-25-hydroxyvitamin D3 in deficient patients might be helpful to relieve symptoms and signs of allergic rhinitis, but further studies are needed.

(23S,25R)-1α,25-Dihydroxyvitamin D3 26,23-lactone (calcitriol lactone) is a major metabolite of 1α,25-dihydroxyvitamin D3 that binds to vitamin D receptor (VDR) and exhibits various biological activities. This lactone and its derivatives are considered to have potential as drug candidates to treat VDR-related diseases, but their biological activities have not yet been fully characterized, mainly because of their limited availability by chemical synthesis. This review deals with synthetic studies of calcitriol lactone, and its derivatives, i.e., methylene lactones (TEI-9647 and its derivatives) and calcitriol lactams (DLAMs). We also discuss their biological activities, VDR-binding affinity and structure-activity relationships.

Herein, we describe a synthetic strategy to access 1α,25-dihydroxyvitamin D3 (calcitriol) analogs with natural or unnatural configuration at C20 and unsaturation at the D-ring. The synthetic approach is exemplified by the synthesis of two potent analogs, namely 1α,25-dihydroxy-16-en-23-yne-vitamin D3 and 1α,25-dihydroxy-20-epi-24a-homo-26,27-dimethyl-vitamin D3. A key feature of the synthetic strategy is the generation of an unnatural configuration at C20 by a catalytic asymmetric reduction of an α,β,γ,δ-unsaturated ester with the CuH species in a micellar system.

A flexible approach to an A-ring building block for new 1α,25-dihydroxyvitamin D analogues functionalized at C-2 as potential clinical candidates is described. The synthesis of alcohol 5 starts from (R)-carvone, and uses a Criegee rearrangement to selectively degrade the isopropenyl side-chain as one of the key steps.

BackgroundThe aim of this study was to investigate whether 1α,25-dihydroxyvitamin D3 can regulate Th17-related immune responses in kidney transplant recipients (KTRs) being treated with tacrolimus (Tac)-based immunosuppression.MethodsFirst, we evaluated the effect of 1α,25-dihydroxyvitamin D3 (1,25(

Herein, we describe a versatile and efficient total synthesis of 1α,25-dihydroxyvitamin D3 (calcitriol). The synthetic strategy relies on an unprecedented Si-assisted SN2′-syn displacement of carbamates by cuprates to set the challenging pivotal quaternary methyl group at the fused-ring junction of the CD-trans-hydrindane core. Other key transformations involve the catalytic asymmetric reduction of an α,β,γ,δ-unsaturated ester with CuH to generate the natural steroidal configuration at C20 and a Pauson–Khand cyclization to form the CD-ring skeleton. This strategy enables the syntheses of novel analogs for structure-function studies and drug development.

The extracellular matrix protein nephronectin (Npnt), also called POEM, is considered to play critical roles as an adhesion molecule in development and functions of various tissues, such as the kidneys, liver, and bone. In the present study, we examined the molecular mechanism of Npnt gene expression and found that vitamin D3 (1α,25-dihydroxyvitamin D3,VD 3) strongly enhanced Npnt mRNA expression in MC3T3-E1 cells from a mouse osteoblastic cell line. The VD 3-induced increase in Npnt expression is both time- and dose-dependent and is mediated by the vitamin D receptor (VDR).

Cigarette smoke extracts (CSE) alter calpain-1 expression via ERK signaling pathway in bronchial epithelial cells. 1α,25-dihydroxyvitamin D3 (1,25D3) inhibits cigarette smoke-induced epithelial barrier disruption. This study was aimed to explore whether the 1,25D3 counteracted the CSE effects in a human bronchial epithelial cell line (16HBE). In particular, transepithelial electrical resistance (TER) and permeability, expression and distribution of E-cadherin and β-catenin, calpain-1 expression, and ERK phosphorylation were assessed in the CSE-stimulated 16HBE cells. The CSE induced the ERK phosphorylation, improved the calpain-1 expression, increased the distribution anomalies and the cleaving of E-cadherin and β-catenin, and resulted in the TER reduction and the permeability increase. The 1,25D3 reduced these pathological changes. The 1,25D3 mediated effects were associated with a reduced ERK phosphorylation. In conclusion, the present study provides compelling evidences that the 1,25D3 may be considered a possible valid therapeutic option in controlling the cigarette smoke-induced epithelial barrier disruption.

Calcitriol analogues which contained an oxime in the side chain were synthesised in five steps from an intermediate 22-nor Ketone. The key intermediate enones were synthesised by the Wittig–Horner olefination and Wittig olefination respectively. Reduction, oximation, photoisomerisation and deprotection gave the target compounds with the oxime at C-24.

It is well established that the mitochondria of proximal convoluted tubule cells of the kidney are the site of production of circulating 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3]. The production of 1,25(OH)2D3 at this site is tightly regulated. Parathyroid hormone markedly stimulates 1,25(OH)2D3 production, whereas 1,25(OH)2D3 itself suppresses production. The mechanism of suppression by 1,25(OH)2D3 has not yet been elucidated. We have now found that in the absence of vitamin D (vitamin D deficiency), the vitamin D receptor (VDR) is found in the interior of the apical brush border of the proximal tubule cells. This is unique for the proximal tubule cells, since this has not been observed in the distal tubule cells or in other epithelial cells, such as intestinal mucosa. Administration of 1,25(OH)2D3 to vitamin D-deficient rats results in the movement of VDR from the brush border to the cytoplasm and nucleus presumably bound to reabsorbed 1,25(OH)2D3. The VDR bound to 1,25(OH)2D3 suppresses expression of 25-hydroxyvitamin D3 1α-hydroxylase and stimulates the 25-hydroxyvitamin D3 24-hydroxylase. Thus, VDR in the apical brush border of the proximal convoluted tubule cells serves to “sense” the level of circulating 1,25(OH)2D3 and modulates the activity of the 1α-hydroxylase and the 24-hydroxylase accordingly.

The aim of this study was to assess the impact of 1α,25-dihydroxyvitamin D3 (vitamin D3) on osteogenic and inflammatory properties of human periodontal ligament (PDL) cells and investigate underlying mechanisms.Human PDL cells, obtained from four subjects, were stimulated with vitamin D3 for 4-48 h. The bone markers osteopontin and osteocalcin and proinflammatory cytokine/chemokine expression was determined by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Cytokine and chemokine expression was determined after stimulation with the inflammation promoter lipopolysaccharide (LPS) in the presence or absence of vitamin D3. Alkaline phosphatase activity was assessed using p-nitrophenylphosphate substrate.Treatment with 30 ng/mL of vitamin D3, corresponding to an optimal plasma concentration of vitamin D, for 24 h had no effect on PDL cell number and morphology but increased PDL cell osteopontin and osteocalcin mRNA expression by about 70 and 40%, respectively, and, moreover, treatment with vitamin D3 for 48 h enhanced PDL cell alkaline phosphatase activity by about two times showing that vitamin D3 exerts pro-osteogenic effects in human PDL cells. Stimulation with LPS (1 μg/mL) for 4 h increased PDL cell interleukin (IL)-6 cytokine and chemokine ligand 1 (CXCL1) chemokine mRNA expression several fold. The LPS-induced increase in IL-6 and CXCL1 transcripts was attenuated by vitamin D3 (30 ng/mL). Treatment with vitamin D3 (3-300 ng/mL) for 24 h reduced the LPS-evoked increase in PDL cell IL-6 protein by about 50%. Vitamin D3 (30 ng/mL) had no effect on LPS-induced IL-1β and MCP-1 mRNA expression.Vitamin D3 promotes osteogenic differentiation but also downregulates inflammation promoter-induced IL-6 cytokine and CXCL1 chemokine expression in human PDL cells, suggesting that vitamin D3 both stimulates bone regeneration and antagonizes inflammation in human periodontal tissue.

Introduction A common problem encountered in routine daily practice of cardiovascular surgery is migration of smooth muscle cells leading to intimal hyperplasia developing at vascular anastomosis sites which then causes luminal narrowing. The aim of this study was to investigate the antiproliferative effect of 1,25 (OH)2D3 on intimal hyperplasia. Material and methods Twenty-one male white New Zealand rabbits weighing 2-3 kg were selected. There were 3 groups of animals each consisting of 7 rabbits. Group 1 was the control group. Group 2 was the sham group and group 3 consisted of rabbits receiving 1,25 (OH)2D3. The right carotid arteries of the subjects in groups 2 and 3 were transected and re-anastomosed. A daily dose of 25 ng 1,25 (OH)2D3 per 100 g body weight was administered for 14 days to rabbits in group 3. Rabbits in group 2 were not subject to any pharmaceutical agent. All the subjects were sacrificed at the end of the 28(th) postoperative day. Their right carotid arteries were resected and then investigated histopathologically. Results Intimal thickness and intimal area were measured as significantly lower in group 1 when compared with the other groups (p = 0.004). In group 3, the ratios of thickness of tunica intima/thickness of tunica media and area of tunica intima/area of tunica media were significantly lower than those of group 2 (p = 0.015, p = 0.003). Conclusions 1,25 (OH)2D3, the active metabolite of vitamin D, reduces the intimal hyperplasia developing after vascular anastomoses.

The synthesis of two new A-ring precursors, useful for the convergent assembly of 2α-ethyl and 2β-ethyl derivatives of 19-nor-1α,25-dihydroxyvitamin D3, is described. These building blocks were prepared in 14 steps from quinic acid, which led to a new and practical synthesis of 2α-ethyl-14-epi-19-nor-20-epi-23-yne-1,25(OH)2D3, an analog that shows a remarkably low calcemic effect in mice, while retaining the ability to promote cell differentiation and to inhibit cell proliferation in a number of human cancer cell lines.

Structure-guided optimization was used to design new analogues of 1α,25-dihydroxyvitamin D3 bearing the main side chain at C12 and a shorter second hydroxylated chain at C17. The new compounds 5a–c were efficiently synthesized from ketone 9 (which is readily accessible from the Inhoffen–Lythgoe diol) with overall yields of 15%, 6%, and 3% for 5a, 5b, and 5c, respectively. The triene system was introduced by the Pd-catalyzed tandem cyclization–Suzuki coupling method. The new analogues were assayed against human colon and breast cancer cell lines and in mice. All new vitamin D3 analogues bound less strongly to the VDR than 1α,25-dihydroxyvitamin D3 but had similar antiproliferative, pro-differentiating, and transcriptional activity as the native hormone. In vivo, the three analogues had markedly low calcemic effects. © 2012 American Chemical Society., We thank the Spanish Ministry of Education and Innovation (SAF2007-67205 and SAF2010-15291 to A. Mouriño, SAF2010-18302 to A. Muñoz, and SAF2009-07631 to RPF) for financial support.

This review highlights the superseding role of mass spectrometry in the structural characterization and quantitation of vitamin D compounds in comparison to other analytical methods (e.g., UV, bioassays) that lack the sensitivity and specificity of mass spectrometry. After a short introduction to the biochemistry of vitamin D compounds, an overview of the current techniques to characterize and quantitate vitamin D compounds is given with emphasis on the contribution of mass spectrometry.

Access to the calcitriol analogues with a tetrazole ring at the side chain was very efficiently achieved using the Calverley-Choudhry approach instead of the Wittig-Horner method, which gave very low yields.

El pdf es la versión de autor.-- et al., An improved synthetic route to 1α,25-dihydroxyvitamin D3 des-side chain analogues 2a and 2b with substituents at C18 is reported, along with their biological activity. These analogues display significant antiproliferative effects toward MCF-7 breast cancer cells and prodifferentiation activity toward SW480-ADH colon cancer cells; they are also characterized by a greatly decreased calcemic profile. The crystal structure of the human vitaminD receptor (hVDR) complexed to one of these analogues, 20(17→18)-abeo-1α,25-dihydroxy-22-homo-21-norvitamin D3 (2a) reveals that the side chain introduced at position C18 adopts the same orientation in the ligand binding pocket as the side chain of 1α,25-dihydroxyvitamin D3. Vitamin D3 supplements: The synthesis and biological activity of des-side chain analogues of 1α,25-dihydroxyvitamin D3 with substituents at C18 are described. Crystallographic analysis revealed that the new side chain introduced at C18 adopts the same orientation as the natural side chain at C17 in the parent molecule 1α,25-dihydroxyvitamin D3. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim., This study was supported by the Spanish Ministry of Education and Science (Grants SAF2004-01885, SAF2007-60341, and SAF2007-67205), the European Union (MRTN-CT-2005-019496, NucSys), the Xunta de Galicia (Projets INCITE08PXIB-209130PR and ACEUIC-2006/XA050), Consolider, Nanobiomed, Fondo de Investigaciones Sanitarias, Fonds voor Wetenschappelijk Onderzoek (FWO) – Vlaanderen (G.553.06 and G.0587.09), CNRS, INSERM, Universit de Strasbourg, ANR, and the European Commission Structural Proteomics in Europe SPINE2-Complexes (LSHG-CT-2006-031220).

A novel approach to the key A-ring α, β-unsaturated aldehyde 1, an important intermediate for the preparation of 1α,25-dihydroxyvitamin D(3), has been developed. The strategy started from the inexpensive starting material (R)-carvone with an ene reaction serving as the key step toward the potential synthesis of vitamin D(3) analogues bearing the modification at the C-2 position.

without a regular family doctor was compared. Results: The mean population number of consultations in 4 weeks was 0.7 per person. The proportion of people who had visited western medicine practitioner, Chinese medicine practitioner and A&E department, prevalence rate in last 4 weeks were 24.6%, 9.5% and 3.7%, respectively. A total of 71.7% had consulted a doctor in the last episode of illness including 65.4% consulting western medicine practitioners, 12.1% Chinese medical practitioners, 7.3% attended A&E department and 3.1% were admitted to the hospital. Over half of last consultations were private western medicine (64.2%) including 59.8% general practices and 4.4% in specialists, whereas over one fifth (23%) of patients visited government-funded general out-patient clinics (15.6%) and specialists (7.4%). Respectively only 8.2% and 2.7% patients had utilised Chinese medicine and other health services at their last consultation. People with a regular family doctor were less likely to use A&E department or hospital service in the last 4 weeks (2.7% vs 5.0%), and less likely to use public services in last consultation (11.1% vs 30.9%). Conclusion: The primary care service utilisation rates in Hong Kong are high compared with countries where primary care is provided by a more unified system. The family doctor–led primary care may reduce the use of A&E department and hospital services.

1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)2D3] directly induces both fusion and cytotoxicity in murine alveolar macrophages. Unlike 1 alpha,25(OH)2D3, retinoic acid per se did not induce fusion of alveolar macrophages, but it greatly enhanced the 1 alpha,25(OH)2D3-induced fusion every time the macrophages were treated simultaneously with the two vitamins. The giant cells induced by the two vitamins were much larger than those induced by 1 alpha,25(OH)2D3 alone. The macrophages treated with 1 alpha,25(OH)2D3 started to fuse 36 h after the addition of the vitamin, whereas the macrophages pretreated with retinoic acid for 24 h began to fuse immediately after 1 alpha,25(OH)2D3 was added. 1 alpha,25(OH)2D3 and retinoic acid activated alveolar macrophages similarly, measured by the enhancement of glucose consumption and the induction of cytotoxicity against tumor cells, though 1 alpha,25(OH)2D3 was 100 times more potent than retinoic acid on a molar basis. Simultaneous treatment with physiological concentrations of 1 alpha,25(OH)2D3 (0.12 nM) and retinoic acid (10 nM) induced cytotoxicity additively. Morphological examinations revealed that the treated cells were enlarged and flattened with numerous filopodia. These results clearly indicate that both 1 alpha,25(OH)2D3 and retinoic acid similarly activate alveolar macrophages, and the activated state is prerequisite to the fusion of macrophages induced by 1 alpha,25(OH)2D3.

In search of analogs of 1α,25-dihydroxyvitamin D3 featuring a dissociation of calcemic and other activities, a series of stereoisomeric 19-nor-22-oxa derivatives, characterized by a spiro[4.5]decane cyclic system instead of the classical CD-ring system, have been synthesized in an enantioselective way.

The discovery that 1 alpha,25-dihydroxyvitamin D-3 is effective in the inhibition of cellular proliferation and in the induction of cellular differentiation has led to a search for analogues in which these activities and the classical calcemic activity of the hormone are dissociated. In this context, the synthesis and biological evaluation are reported for six CD-ring modified structural analogues that were conceived so as to enforce a particular orientation of the 25-hydroxylated side chain. The analogues are characterized by the absence of the C-ring and the presence of an unnatural six-membered D-ring. The biased side-chain orientations are realized through the stereocontrolled incorporation of methyl substituents at positions C13/C20 and C16/C20. Comparison of the results of the biological evaluation and conformational analysis of the side chain confirms the existence of a relationship between inhibition of MCF-7 breast cancer cell proliferation and side chain geometry. ((c) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

A mild and stereoconvergent synthesis of 1α25-dihydroxyvitamin D 3 (calcitriol, la) is described. The key step is a cascade process consisting of two consecutive transformations: An initial palladium-catalyzed 6-exo-cyclocarbopalladation of vinyl triflate 4 followed by a Negishi cross-coupling reaction with alkenyl zinc 3. This approach is of interest for the rapid synthesis of a variety of new vitamin D 3 analogues of therapeutic potential, especially those modified at the triene and ring-A. The mildness of the method also allows the preparation of thermal sensitive vitamin D 3 analogues.

Replacing the 1alpha-OH group of the natural hormone 1alpha,25-dihydroxyvitamin D(3) (calcitriol) by a 1alpha-CHF(2) group and incorporating a potentiating side chain produced two new hybrid analogs 6 and 7. Both of these two hybrid analogs are as transcriptionally active as calcitriol and are strongly antiproliferative in vitro but are low-calcemic in vivo.

The synthesis of several 19-nor-2-alkyl-1α,25-dihydroxyvitamin D3 analogues (5–14) is described following the cyclovitamin strategy. Starting from all-cis methyl 3,5-dihydroxy-4-alkyl-1-cyclohexanecarboxylate (29), the eight stereoisomeric A-ring-precursor 2-tert-butyldiphenylsilyloxy-3α-formyl-1-alkylbicyclo[3.1.0]hexanes (39, 44, 46, 63, 65, 67, 69, 71) were prepared in two series: a (R = methyl) and b (R = ethyl). In particular, from the coupling of 39 and the lithiated compounds derived from the CD-ring bromides 20 and 21 possessing the natural or the 23-yne side chain, the title derivatives 5–14 were synthesized. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

We synthesized all eight possible A-ring diastereomers of 2-methyl substituted analogs of 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3] and also all eight A-ring diastereomers of 2-methyl-20-epi-1alpha,25(OH)2D3. Their biological activities, especially the antagonistic effect on non-genomic pathway-mediated responses induced by 1alpha,25(OH)2D3 or its 6-s-cis-conformer analog, 1alpha,25(OH)2-lumisterol3, were assessed using an NB4 cell differentiation system. Antagonistic activity was observed for the 1beta-hydroxyl diastereomers, including 2beta-methyl-1beta,25(OH)2D3 and 2beta-methyl-3-epi-1beta,25(OH)2D3. Very interestingly, 2beta-methyl-3-epi-1alpha,25(OH)2D3 also antagonized the non-genomic pathway, despite its 1alpha-hydroxyl group. Other 1alpha-hydroxyl diastereomers did not show antagonistic activity. 20-epimerization diminished the antagonistic effect of all of these analogs on the non-genomic pathway. These findings suggested that the combination of the 2-methyl substitution of the A-ring and 20-epimerization of the side chain could alter the biological activities in terms of antagonism of non-genomic pathway-mediated biological response. Based on a previous report, 2-methyl substitution alters the equilibrium of the A-ring conformation between the alpha- and beta-chair conformers. The 2beta-methyl diastereomers, which exhibited antagonism on non-genomic pathway-mediated response, were considered to prefer the beta-conformer. Further examination to elucidate the relationship between the altered ligand shape and receptors interaction will be important for molecular level understanding of the mechanism of antagonism of the non-genomic pathway.

Vitamin D3 analogs are potential anti-cancer agents with theoretically wide therapeutic index, but there have been limited studies directed towards human neuroblastoma. The antiproliferative ability of the novel vitamin D3 hybrid analog QW-1624F2-2 (QW, 1-hydroxymethyl-16-ene-24, 24-F2-26, 27-bishomo-25-hydroxyvitamin D3) was examined in two human neuroblastoma-derived cell-lines. Analog QW inhibited cell-cycle progression of IMR5 cells with accumulation in G1 phase. QW induced the differentiation of CHP134 as evidenced by increased neurite length. These effects were accompanied by decreased expression of MYCN in both the cell-lines treated with QW. Furthermore, QW inhibited the migration of CHP134 cells in matrigel invasion assays, indicating its anti-invasive ability. In athymic nude mice, we found that QW was less calcemic than EB1089 (1α, 25-dihydroxy-22, 24-diene-24, 26,27-trishomovitamin D3). Systemic administration of QW in a mouse xenotransplantation model revealed that it is more effective than EB1089 in suppressing the growth of CHP134 flank tumors. In summary, the low-calcemic hybrid analog QW showed significant anti-tumor activity in vivo and thus exhibits potential as a novel cancer therapeutic. © 2005 Wiley-Liss, Inc.

Two 21-nor-22-oxa-1α,25-dihydroxyvitamin D 3 derivatives have been synthesized in quest of a drug with lower calcemic activity than Maxacalcitol, 22-oxa-1α,25-dihydroxyvitamin D 3 , being used as antihyperparathyroidism and antipsoriatic drug. Of two 21-nor products obtained, the product carrying one carbon elongated side chain with diethylcarbinol moiety has been found to exhibit comparable differentiation-inducing activity to Maxacalcitol with much lower exhibition of calcemic activity.

Based on an X-ray crystal structure determination, the A-ring stereochemistry of hybrid analog QW-1624F2-2 (1alpha-hydroxymethyl-16-ene-24,24-difluoro-25-hydroxy-26,27-bis-homovitamin D3) is revised to be 1alpha-CH2OH-3beta-OH. This analog is shown to be approximately 80-100 times less calciuric than the natural hormone 1alpha,25-dihydoxyvitamin D3. This analog is shown also to be non-genotoxic in three different standard assays.

A concise and efficient synthetic approach to 2 alpha-(omega-hydroxyalkoxy)-1 alpha,25-dihydroxyvitamin D(3) (4a-c), including 2-epi-ED-71, was developed starting from D-glucose as a chiral template for the construction of the 2 alpha-modified A-ring precursors (11a-c). It was found that the best ligand for the bovine thymus vitamin D receptor (VDR) in this series is 4b, which has 1.8 times greater binding affinity for the bovine thymus VDR than that of the natural hormone 1. Interestingly, potency in the induction of HL-60 cell differentiation for 4a-c was almost the same or weaker than that of 1 despite the strong binding affinity for the VDR. Next, we were interested in the "double modification"of 1 based on 4a-c with C20-epimerization, affording 2 alpha-(omega-hydroxyalkoxy)-20-epi-1 alpha,25-dihydroxyvitamin D(3) (20-epi-4a-c). All three 2 alpha-substituted 20-epi analogues of 1 (20-epi-4a-c) exhibited stronger binding affinities for the VDR, and their conformations in the ligand binding domain of VDR were analyzed by molecular modeling. Double-modified analogues of 20-epi-4a-c showed marked HL-60 cell differentiation activity, and 20-epi-4a possesses an activity 58-fold higher than that of the natural hormone 1.

The metabolism of 1alpha,25(OH)(2)D(3) (1alpha,3beta) and its A-ring diastereomers, 1beta,25(OH)(2)D(3) (1beta,3beta), 1alpha,25(OH)(2)-3-epi-D(3) (1alpha,3alpha), and 1beta,25(OH)(2)-3-epi-D(3) (1beta,3alpha), was examined to compare the substrate specificity and reaction specificity of CYP24A1 between humans and rats. The ratio between C-23 and C-24 oxidation pathways in human CYP24A1-dependent metabolism of (1alpha,3alpha) and (1beta,3alpha) was 1:1, although the ratio for (1alpha,3beta) and (1beta,3beta) was 1:4. These results indicate that the orientation of the hydroxyl group at the C-3 position determines the ratio between C-23 and C-24 oxidation pathways. A remarkable increase of metabolites in the C-23 oxidation pathway was also observed in rat CYP24A1-dependent metabolism. The binding affinity of human CYP24A1 for A-ring diastereomers was (1alpha,3beta)(1alpha,3alpha)(1beta,3beta)(1beta,3alpha), indicating that both hydroxyl groups at C-1 and C-3 positions significantly affect substrate-binding. The information obtained in this study is quite useful for understanding substrate recognition of CYP24A1 and designing new vitamin D analogs.

Novel analogues of the hormone 1alpha,25-(OH)(2)-D(3) with side chains attached to C-18 were synthesized by a versatile route in which key steps were the remote radical-induced functionalization of the 18-methyl by the C-8beta-hydroxyl group and the introduction of the side chains by Wittig reactions on a C-18-aldehyde. The triene system of the novel analogues was constructed by the convergent Lythgoe-Hoffmann la Roche approach, which involves reaction of a phosphine oxide (the ring A fragment) with a ketone (the upper fragment).

Novel vitamin D(3) analogs having a lactam structure in their side chains, 1 alpha,25-dihydroxyvitamin D(3)-26,23-lactams (DLAMs), were designed based on the principle of regulation of the folding of helix-12 in the vitamin D nuclear receptor (VDR). The new analogs were synthesized via 1,3-dipolar cycloaddition reaction and subsequent reduction of the isoxazolidine as key steps. Among the analogs, (23S,25S)-DLAM-01 (4a) and (23S,25S)-DLAM-1P (5a) bind strongly to VDR. Moreover, these analogs were found to inhibit the differentiation of HL-60 cells induced by 1 alpha,25-dihydroxyvitamin D(3).

The present study was carried out to evaluate the effects of 1α,25-dihydroxyvitamin D3 (VD) on chromosomal aberrations induced by doxorubicin (DXR). Wistar rats were divided into eight experimental groups of five animals each. Control group animals were treated with i.p. distilled water. The animals in three VD groups were given only VD for 4, 6 or 8 weeks. In the DXR groups the animals were given only DXR. In the combination groups VD doses were given for 4, 6 or 8 weeks for each group and DXR was injected 24 h before sacrificing the rats. DXR (50 mg/100 g b.w.) was injected intraperitoneally and VD by gavage 3 μg/kg/day twice weekly. Animals treated with both VD and DXR showed a low frequency of chromosomal aberrations and abnormal metaphases when compared with animals treated with DXR alone (p 0.05) and lower than those in week 4 for the VD groups (p

Objective: Calcitriol, 1α,25-dihydroxyvitamin D3 (1,25-D3) has potent antiproliferative effects and potentiates the antitumor activity of many other cytotoxic drugs. 1,25-D3 plasma pharmacokinetic (PK) parameters associated with antitumor activity in experimental animal models are unknown. The objective of this study was to determine plasma calcitriol PK in normal mice at doses of calcitriol which are active in suppressing tumor growth. Methods: Plasma 1,25-D3 PK were examined in normal C3H/HeJ mice after a single intraperitoneal dose of 0.125 or 0.5 µg 1,25-D3/mouse. PK blood samples were collected from groups of 5–9 mice at each time point up to 24 h after 1,25-D3 administration. Plasma 1,25-D3 concentrations were measured by radioimmunoassy. Plasma 1,25-D3 concentration diurnal variation was determined in blood samples from untreated animals collected in the morning (9:00–11:00 a.m.) and in the evening (4:00–9:00 p.m.). Results: Median baseline plasma 1,25-D3 concentration measured in the morning and in the evening were 0.082 ng/ml (CI 95%, 0.076–0.099) and 0.067 ng/ml (CI 95%, 0.058–0.075), respectively (p = 0.004). After 0.125 and 0.5 µg dosing, peak plasma 1,25-D3 concentrations (Cpmax) were 12.0 ng/ml (CI 95%, 10.8–12.6) and 41.6 ng/ml (CI 95%, 40.8–53.6), respectively. The corresponding areas under the curve (AUC0–>24 h) were 47.0 (CI 95%, 43.2–51.1) and 128.0 (CI 95%, 127.0–130.0) ng·h/ml. No dose-related changes in time to Cpmax and apparent total plasma clearance were observed. Conclusions: These results demonstrate diurnal variation in baseline plasma 1,25-D3 concentrations in mice. Plasma 1,25-D3 PK in mice receiving doses that are effective in slowing tumor growth, inducing cell cycle arrest and apoptosis, and potentiating taxanes and platinum analogue antitumor activity are at least 5–10 times higher than those easily achieved and nontoxic in patients receiving high-dose intermittent oral therapy.

Vitamin D3 and its synthetic analogs are promising compounds for controlling various types of cell differentiation. In this article, we describe the synthesis of novel vitamin D3 analogs containing heteroatoms in their side chains – so-called vitamin D3 lactam analogs – via 1,3-dipolar cycloaddition reaction as a key step.

We present our first results on the synthesis of a new class of conformationally restricted vitamin D analogues bearing an extra five-membered ring formed by linking C(18) and C(21). Two analogues of calcitriol (1) with unsaturations at the extra ring and the lateral chain were prepared. The triene system was introduced by the convergent Wittig-Horner approach developed by Lythgoe [8] and F Hoffmann-La Roche [9]. The key steps in the preparation of the requisite fragments were: i) the long-distance functionalization of ketal 11 at C(18), ii) the ring closure on 15 through an intramolecular aldol condensation to give the α,β-unsaturated ketone 10, and iii) the Pd-catalyzed installation of the side chains.

The synthesis and biological activities of seco C-9,11,21-trisnor-17-methyl-1 alpha,25-dihydroxyvitamin D(3) analogues (D-ring analogues) are described.

1α,25-Dihydroxyvitamin D3, the hormonal form of vitamin D3, is widely appreciated to play a central role in calcium and phosphorous homeostasis. It is becoming increasingly clear, however, that the sterol also plays an important role in the regulation of cellular growth, central nervous system function, and immune responsiveness. In this review, I will highlight some of the mechanisms by which 1α,25-dihydroxyvitamin D3 regulates cellular growth, alters central nervous system function, and immune function.

In the present study, the chemopreventive effect of the active metabolite of vitamin D, 1α,25-dihydroxyvitamin D3 (VD3), against chemically-induced and diabetes-promoted rat liver carcinogenesis was investigated. Hepatocarcinogenesis was initiated with a single intraperitoneal (i.p.) injection of diethylnitrosamine (DEN) (125 mg kg−1 body weight) at week 4 followed by promotion with streptozotocin (STZ) (65 mg kg−1 body weight with a single i.p. injection) at week 7. With this basic experimental regimen, the effect of VD3 (0.3 μg (0.1 ml)−1 propylene glycol per os twice a week) was investigated with effect from 4 weeks prior to the exposure of DEN. The results showed that VD3 supplementation throughout the experimental period reduced the incidence, total number and multiplicity and altered the size of visible persistent nodules (PNs) in DEN- or DEN + STZ-treated rats as compared with their respective controls. In these two groups, it also caused a significant decrease in the number (p

Vitamin D receptor (VDR) regulates the expression of a broad array of genes, including those involved in drug biotransformation (e.g. CYP2B6). Ginkgo biloba extract induces CYP2B6, but it is not kn...

In Figure 9B, the upper panel showing the phospho-p38 signals, is turned upside down. The correct Figure 9B can be found at the following link