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Vitamin D5
Vitamin D5
Vitamin D5
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Vitamin D5
Names
IUPAC name
(1S,3Z)-3-[(2E)-2-[(1R,3aS,7aR)-1-[(1R,4S)-4-ethyl-1,5-dimethylhexyl]-7a-methyl-2,3,3a,5,6,7-hexahydro-1H-inden-4-ylidene]ethylidene]-4-methylene-1-cyclohexanol
Other names
Sitocalciferol
(5Z,7E)-(3S)-9,10-secoporiferasta-5,7,10(19)-trien-3-ol
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
UNII
  • InChI=1S/C29H48O/c1-7-23(20(2)3)12-10-22(5)27-16-17-28-24(9-8-18-29(27,28)6)13-14-25-19-26(30)15-11-21(25)4/h13-14,20,22-23,26-28,30H,4,7-12,15-19H2,1-3,5-6H3/b24-13+,25-14-/t22-,23+,26+,27-,28+,29-/m1/s1 checkY
    Key: RMDJVOZETBHEAR-GHTRHTQZSA-N checkY
  • InChI=1/C29H48O/c1-7-23(20(2)3)12-10-22(5)27-16-17-28-24(9-8-18-29(27,28)6)13-14-25-19-26(30)15-11-21(25)4/h13-14,20,22-23,26-28,30H,4,7-12,15-19H2,1-3,5-6H3/b24-13+,25-14-/t22-,23+,26+,27-,28+,29-/m1/s1
    Key: RMDJVOZETBHEAR-GHTRHTQZBN
  • O[C@@H]1CC(\C(=C)CC1)=C\C=C2/CCC[C@]3([C@H]2CC[C@@H]3[C@H](C)CC[C@H](CC)C(C)C)C
Properties
C29H48O
Molar mass 412.702 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

Vitamin D5 (sitocalciferol) is a form of vitamin D.

Research

[edit]

Analogs of calcitriol, a form of vitamin D3, have been proposed for use as antitumor agents.[1][2][3] Studies on vitamin D3 have shown inhibition of cell proliferation in prostate cancer, but high doses of vitamin D3 result in hypercalcemia. The effects of vitamin D5 on prostate cancer have also been studied, and unlike vitamin D3, vitamin D5 does not cause hypercalcemia while inhibiting tumor cell proliferation.[4] The most researched analogue of vitamin D5 as an antitumor agent is 1α-hydroxyvitamin D5.

1α-Hydroxyvitamin D5

[edit]

1α-Hydroxyvitamin D5 is a chemical derivative of vitamin D5. The motive to study 1α-hydroxyvitamin D5 as a potential pharmaceutical drug stemmed from the tendency of calcitriol, a natural metabolite produced in the kidney, to cause toxic hypercalcemia in patients when dosed at concentrations needed to interrupt prostate cancer cells' cycle and stimulate apoptosis.[5][6] And while supplementation with dexamethasone decreases hypercalcemia,[7] bypassing it with an equally effective tumor suppressant would reduce patient cost and stress. Thus, the therapeutic effects of 1α-Hydroxyvitamin D5 as a potential antitumor agent without the side effects of calcitriol became a topic of study.

1α-Hydroxyvitamin D5 was first synthesized in 1997 by researchers in the Department of Chemistry at the University of Chicago, under Robert M. Moriarty and Dragos Albinescu. By 2005, the group had revised its synthesis method for a more streamlined, higher yield-producing route. It involved the photochemical conversion of precursor 7-dehydrositosteryl acetate to contain a conjugated triene system, a hallmark of this analog, followed by hydroxylation, photoisomerization, and deprotection steps. Their overall yield was 48%.[8]

See also

[edit]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Vitamin D5

View on Grokipedia
from Grokipedia
Vitamin D5, also known as sitocalciferol, is a and a lesser-known member of the family with the molecular formula C₂₉H₄₈O and the systematic name (3β,5Z,7E)-9,10-seco-5α-stigmasta-5,7,10(19)-trien-3β-ol. It features a at position 17 identical to that of β-sitosterol (featuring a 24-ethyl group), distinguishing it from more common forms like vitamin D₂ () and vitamin D₃ (cholecalciferol). This compound is primarily synthetic, derived from the (UV) irradiation of precursors such as 7-dehydrositosterol or β-sitosterol, and it plays a role in metabolism pathways similar to other analogs. Although predominantly produced artificially, vitamin D5 has been identified in natural settings, particularly in the model plant , where it forms as a UV-B-mediated derivative of the sterol intermediate 7-dehydrositosterol in mutants like dwarf5. Its presence in plants suggests a potential ecological role in response to radiation, though its physiological function in remains unclear and does not appear to replicate the calcium effects seen in vertebrates. In laboratory contexts, vitamin D5 is solubilized in mixed micelles for intestinal uptake studies, where its absorption by human intestinal cells (e.g., models) is lower than that of vitamins D₂, D₃, D₄, D₆, and D₇, but can be enhanced approximately 2.5-fold by . Biologically, D5 exhibits vitamin D-like activity but with significantly reduced potency compared to established forms; it is approximately 100 times less effective in inducing calcium mobilization and 80 times less active in stimulating intestinal calcium transport relative to vitamin D₃. Its antirachitic activity in animal models, such as rats, is about 1/180th that of vitamin D₃, limiting its role in preventing conditions like . However, activated derivatives like 1α-hydroxyvitamin D5 demonstrate promising antiproliferative effects against cancers (e.g., , , and colon) with lower risks of hypercalcemia than vitamin D₃ analogs, highlighting potential therapeutic applications in . Computational predictions suggest vitamin D5 may support formation and act as a , though clinical exploration remains limited due to its lower efficacy in classical calcium regulation pathways.

Chemistry

Molecular Structure

Vitamin D5, also known as sitocalciferol, is a derivative characterized by a steroid backbone with a cleaved bond between carbons 9 and 10, resulting in an open B-ring structure typical of all compounds. This features a conjugated triene system involving double bonds at positions 5-6, 7-8, and 10(19), which contributes to its characteristic UV absorption and biological precursor role, along with a hydroxyl group at carbon 3 that imparts polarity to the molecule. The attached at position 17 is a (5R)-5-ethyl-6-methylheptan-2-yl group, distinguishing it from other forms and derived from the plant sterol sitosterol. The systematic IUPAC name for Vitamin D5 is (1S,3Z)-3-[(2E)-2-[(1R,3aS,7aR)-1-[(1R,4S)-4-ethyl-1-methylheptyl]-7a-methyl-2,3,3a,5,6,7-hexahydro-1H-inden-4-ylidene]ethylidene]-4-methylidenecyclohexan-1-ol, reflecting its complex and ring fusions. Its molecular formula is C₂₉H₄₈O, with a molecular weight of 412.7 g/mol, accounting for 29 carbon atoms, 48 hydrogens, one oxygen, and the appropriate from the triene and exocyclic methylene. In comparison to other major vitamin D variants, D5's includes an at carbon 24, a feature inherited from its precursor 7-dehydrositosterol, unlike D3 (cholecalciferol), which derives from and has a simpler 6-methylheptan-2-yl chain without the C24 , or D2 (ergocalciferol), sourced from and featuring a between carbons 22 and 23 along with a methyl at C24. This C24 in D5 extends the length and alters its steric properties, potentially influencing receptor interactions and metabolic processing compared to the more common D2 and D3 forms. The core structure, however, remains conserved across these analogs, with the open B-ring, triene conjugation, and C3 hydroxyl defining the vitamin D scaffold.

Nomenclature and Properties

Vitamin D5, also known as sitocalciferol, is a member of the family derived historically from the ultraviolet irradiation of β-sitosterol, serving as a provitamin form analogous to other variants. Its systematic name reflects the structure with a side chain featuring an ethyl group at C24, distinguishing it from more common forms like cholecalciferol (). The compound is identified by CAS number 71761-06-3 and CID 9909623. Physically, vitamin D5 presents as an off-white to light yellow crystalline powder with a reported melting point of 105–106 °C. It is insoluble in , consistent with its fat-soluble nature, but exhibits solubility in organic solvents such as , , and (DMSO). Chemically, vitamin D5 features a conjugated triene system in its structure, responsible for ultraviolet (UV) absorption maxima at approximately 265 nm. This moiety confers sensitivity to and heat, promoting to tachysterol or lumisterol under such conditions. Regarding stability, the compound remains relatively stable at neutral (above 5) and under cool, dry storage (0–8 °C), but is susceptible to degradation via oxidation, particularly in the presence of air or trace metals.

Sources

Natural Occurrence

Vitamin D5, also known as sitocalciferol, is primarily derived in natural environments through the ultraviolet B (UVB) of 7-dehydrositosterol (7-DHS), a common biosynthetic intermediate in the production of sitosterol, the most abundant in . This photoconversion process breaks the B-ring of 7-DHS, forming previtamin D5 that thermally isomerizes to vitamin D5, occurring specifically in plant tissues exposed to . Unlike vitamins D2 and D3, which arise from fungal and animal precursors respectively, vitamin D5 is tied to plant pathways and is not synthesized in animals. The natural occurrence of vitamin D5 was first documented in 2018 in the model plant , particularly in the leaves of the dwarf5 mutant, where UVB exposure led to its accumulation as a derivative of 7-DHS decay. In these studies, 7-DHS levels dropped from approximately 42% to 14% of total sterols after seven days of UVB treatment, with vitamin D5 detected at peak intensities up to 50 times higher via liquid chromatography-mass spectrometry analysis. Trace amounts may form endogenously without intense irradiation, but significant production requires UVB stimulation. While the biosynthetic pathway suggests potential occurrence in other sitosterol-containing plants, vitamin D5 has only been empirically detected in as of 2025. It is absent or exceedingly rare in animal sources, as 7-DHS is not a component of animal biosynthesis, distinguishing it from the cutaneous production of D3 in vertebrates. Environmental factors play a critical role in D5 production, with effective photoconversion requiring UVB wavelengths between 280 and 315 nm, and optimal dosages such as 280 µJ/cm² at 302 nm applied intermittently (e.g., 5 minutes hourly) to mimic natural without excessive degradation. Higher latitudes or shaded conditions reduce formation, limiting its natural abundance to sun-exposed plant surfaces in equatorial or temperate regions.

Synthesis Methods

Vitamin D5, also known as sitocalciferol, is primarily synthesized through photochemical methods involving (UV) irradiation of its provitamin precursor, 7-dehydrositosterol. This process mimics the natural photoconversion seen in other analogs but is conducted under controlled conditions to produce the secosteroid structure via electrocyclic ring opening of the B-ring in the precursor . The reaction typically employs UV light in the 265-280 nm range, generating previtamin D5 as an intermediate, which then undergoes thermal to yield the thermodynamically stable Vitamin D5. The synthesis begins with β-sitosterol, a common , as the starting material. The process involves selective allylic oxidation at the C-7 position to form 7-dehydrositosterol, often achieved through a sequence of protection (e.g., of the 3-hydroxy group with in ), bromination with N-bromosuccinimide, debromination with tetrabutylammonium fluoride, and deprotection with . Subsequent UV irradiation of the provitamin (e.g., at 280 nm with an intensity of 9.03 mW/cm² for 4 hours) produces previtamin D5 in yields of approximately 28%, followed by heating at 100°C for 1 hour to isomerize it to Vitamin D5 with about 39% efficiency from the previtamin. Overall yields for Vitamin D5 from β-sitosterol range from 20-40%, depending on optimization, though side products such as lumisterol and tachysterol derivatives can form, requiring careful control of irradiation conditions. Purification of Vitamin D5 typically involves silica-gel using /n-hexane (3:7) mixtures, followed by reverse-phase (HPLC) on a C-18 column with as the mobile phase, achieving isolation with retention times around 88.9 minutes. Challenges include the separation of structurally similar vitamin D analogs (e.g., D2, D4, D6, D7) when synthesized simultaneously from mixed phytosterols, often necessitating multiple HPLC runs and resulting in modest isolated yields (e.g., 11.3 mg of Vitamin D5 from 53.31 mg previtamin). The first reported of Vitamin D5 occurred in the late 1970s as part of early research into analogs. Alternative routes include modified photochemical approaches using two-wavelength photolysis to enhance B-ring opening efficiency and total syntheses starting from non-steroidal or basic steroid intermediates, though the sitosterol-based method remains the most widely adopted for laboratory-scale production. These methods are primarily scalable for research applications, such as studying vitamin D structure-activity relationships, rather than industrial supplementation due to cost and yield limitations.

Biological Role

Metabolism in Organisms

Vitamin D5, like other fat-soluble vitamin D analogs, is absorbed primarily in the through passive facilitated by mixed micelles formed from salts, monoglycerides, free fatty acids, and phospholipids. These micelles solubilize the hydrophobic Vitamin D5, enabling its uptake across the . is limited without micellar solubilization, but incorporation into mixed micelles significantly enhances absorption efficiency. In vitro studies using differentiated human intestinal cells, a model for uptake, demonstrate that the uptake of vitamins D4, D6, and D7 is similar to D2 and D3, but vitamin D5 uptake is lower, with no statistically significant differences among D2–D4 and D6–D7 (p > 0.05). The presence of in these micelles further boosts cellular uptake by approximately 2.5-fold, likely by reducing content in tight junctions and improving paracellular permeability. Approximately 20% of this uptake occurs via involving the Niemann-Pick C1-like 1 (NPC1L1) transporter. Following absorption, Vitamin D5 is transported via the to the liver, where it undergoes 25-hydroxylation primarily by the enzyme CYP2R1 to produce 25-hydroxyvitamin D5, the major circulating form. This step is relatively non-regulated and occurs efficiently in hepatocytes. The 25-hydroxyvitamin D5 is then released into the bloodstream, bound to vitamin D-binding protein, and delivered to target tissues. The of 25-hydroxyvitamin D5, consistent with other vitamin D metabolites, is approximately 2-3 weeks, allowing for sustained circulating levels. In the kidneys, 25-hydroxyvitamin D5 is further activated through 1α-hydroxylation by the enzyme CYP27B1 (also known as 1α-hydroxylase) to form 1,25-dihydroxyvitamin D5, the hormonal analog of . This tightly regulated step depends on factors such as levels and serum calcium/phosphate status. Due to structural differences in its —specifically, an at the C24 position compared to the cholesterol-derived of Vitamin D3—Vitamin D5 shows reduced metabolic efficiency and biological potency. It is approximately 180-fold less active than Vitamin D3 in stimulating rachitic cartilage calcification, 80-fold less effective in promoting intestinal calcium absorption, and 100- to 200-fold less effective in calcium mobilization in vitamin D-deficient rat models. Inactive metabolites of Vitamin D5, including hydroxylated forms, are primarily excreted through the biliary route into the feces as water-soluble conjugates such as glucuronides and sulfates, with minor urinary elimination. These conjugation reactions, mediated by UDP-glucuronosyltransferases and sulfotransferases in the liver, facilitate elimination and prevent reabsorption. Enterohepatic recirculation may occur to a limited extent, but the majority of processed Vitamin D5 is ultimately lost via fecal excretion.

Physiological Functions

Vitamin D5, also known as sitocalciferol, exhibits physiological functions analogous to other isoforms, primarily through binding to the (VDR) after metabolic activation to its hydroxylated form. This activation, involving 25-hydroxylation in the liver followed by 1α-hydroxylation in the , enables it to regulate calcium and homeostasis, though with substantially reduced potency compared to vitamin D3 (cholecalciferol). In calcium and phosphate regulation, activated vitamin D5 promotes intestinal calcium absorption and bone mineralization by interacting with the VDR to induce the expression of transport proteins such as and TRPV6. However, its activity is markedly lower than that of vitamin D3; specifically, it is approximately 80-fold less effective in stimulating intestinal calcium transport and about 100-fold less active in inducing bone calcium mobilization. The structural difference in its —an at C-24 compared to the in vitamin D3—likely contributes to this reduced VDR affinity and overall calcemic response. In plants, particularly in the Arabidopsis thaliana, vitamin D5 accumulates in the dwarf5 mutant under UV-B exposure through photoconversion of the precursor 7-dehydrositosterol, suggesting a potential role in UV protection by dissipating excess energy or in maintaining homeostasis by modulating precursor levels. This accumulation reduces 7-dehydrositosterol from 42% to 14% of total after seven days of UV-B treatment, though its exact contribution to remains unconfirmed. Such functions have not been established in mammals. Due to its rarity in natural dietary sources and limited biological availability, no established daily requirements for vitamin D5 exist in humans.

Research

Derivatives and Analogs

1α-Hydroxyvitamin D5 is a synthetic analog of vitamin D5 featuring a hydroxyl group at the 1α position, which serves as a capable of bypassing the renal step required for activation of the parent compound. Developed in the , this analog was initially explored for potential applications in renal due to its reduced calcemic effects compared to fully hydroxylated forms like . The addition of the 1α-hydroxyl group at the C1 position enhances its binding affinity to the (VDR), though it exhibits lower potency than 1,25-dihydroxyvitamin D3, with an IC50 of approximately 100 pM versus 0.08 pM for the latter. The molecular formula of 1α-hydroxyvitamin D5 is C29H48O2, with a molecular weight of 428.7, and it is characterized by a of 145-146°C and a UV maximum at 265 nm. This structural modification allows the analog to undergo tissue-specific , such as conversion to 1,24- or 1,25-dihydroxyvitamin D5 in target tissues like cells, without relying on function. Among other analogs, 25-hydroxyvitamin D5 functions as a key metabolic intermediate in the activation pathway of vitamin D5, formed via hepatic hydroxylation and serving as a precursor to more active forms. Research has occasionally referenced fluorinated or side-chain modified variants of vitamin D5, such as those incorporating fluorine at C24 or alterations to the ethyl-substituted side chain, primarily for investigative purposes in metabolic stability studies, though these remain less characterized than their vitamin D3 counterparts. Derivatives of vitamin D5, including its hydroxylated forms, are typically synthesized through chemical methods post-production of the base vitamin D5 from precursors like or β-sitosterol, involving steps such as photolysis, thermolysis, and selective using reagents like those in the Paaren-DeLuca procedure. Vitamin D5 was first synthesized in 1979. Enzymatic approaches, utilizing enzymes like CYP27B1, can also introduce the 1α-hydroxyl group to suitable precursors, offering a biomimetic route for analog preparation. These analogs often demonstrate improved stability when stored at low temperatures, such as -75°C, and enhanced solubility for therapeutic formulations when dissolved in vehicles like or .

Clinical and Experimental Studies

Clinical and experimental studies on Vitamin D5 (sitocalciferol) have primarily focused on its absorption, plant-specific roles, and potential therapeutic applications, though human data remain sparse due to the compound's limited availability. A 2021 in vitro study examined the uptake of vitamins D2 through D7, solubilized in mixed micelles, by human intestinal cells, a model for intestinal absorption. The results demonstrated that vitamin D5 uptake was lower than that of vitamins D4 and D6, with enhancing cellular incorporation across all forms, indicating potential implications for dietary supplementation strategies. In plant biology, research has identified Vitamin D5 as a UV-B-induced in . A 2018 study using LC-MS analysis of the dwarf5 mutant showed that UV-B exposure increased Vitamin D5 levels by approximately 50-fold, derived from the conversion of provitamin 7-dehydrositosterol, suggesting a possible role in photoprotection or metabolism under stress conditions; however, this has no established dietary significance for human nutrition. Exploration of Vitamin D5's therapeutic potential has centered on its lower calcemic profile compared to Vitamin D3, particularly through derivatives like 1α-OH-D5. Preclinical studies in the 1990s and 2000s demonstrated that 1α-OH-D5 exhibits antiproliferative effects in , , and colon cancer models while inducing less hypercalcemia than 1,25(OH)₂D₃ at equivalent doses, positioning it as a candidate for interventions with reduced risk of calcium-related . No instances of hypercalcemia were reported in these and cell-based assessments at doses paralleling those of standard vitamin D forms, though human clinical trials are scarce owing to synthesis challenges and limited commercial interest. Knowledge gaps persist, particularly in Vitamin D5's metabolism and long-term safety in humans, with most research after 2018 including both plant-derived contexts and in vitro studies on intestinal uptake, rather than advancing to clinical applications as of 2025.

References

  1. https://www.mdpi.com/2227-9059/13/4/1002
  2. https://www.nature.com/articles/s41598-018-34775-z
  3. https://pmc.ncbi.nlm.nih.gov/articles/PMC8067314/
  4. https://pubchem.ncbi.nlm.nih.gov/compound/Vitamin-D5
  5. https://www.chemspider.com/Chemical-Structure.7826639.html
  6. https://pmc.ncbi.nlm.nih.gov/articles/PMC12025311/
  7. https://pubchem.ncbi.nlm.nih.gov/compound/9909623
  8. https://www.bocsci.com/product/vitamin-d5-cas-71761-06-3-453668.html
  9. https://pmc.ncbi.nlm.nih.gov/articles/PMC8701098/
  10. https://pmc.ncbi.nlm.nih.gov/articles/PMC8147103/
  11. https://onlinelibrary.wiley.com/doi/10.1155/2021/5599140
  12. https://pmc.ncbi.nlm.nih.gov/articles/PMC5331567/
  13. https://pmc.ncbi.nlm.nih.gov/articles/PMC6630616/
  14. https://pubs.acs.org/doi/10.1021/jo050853f
  15. https://pubmed.ncbi.nlm.nih.gov/232394/
  16. https://www.ncbi.nlm.nih.gov/books/NBK278935/
  17. https://pmc.ncbi.nlm.nih.gov/articles/PMC2665033/
  18. https://www.sciencedirect.com/science/article/pii/0003986179902261
  19. https://pubmed.ncbi.nlm.nih.gov/2104249/
  20. https://doi.org/10.1016/0003-9861(79)90226-1
  21. https://doi.org/10.1038/s41598-018-34775-z
  22. https://apps.dtic.mil/sti/tr/pdf/ADA432552.pdf
  23. https://patents.google.com/patent/US6900191B1/en
  24. https://www.caymanchem.com/product/9000683/25-hydroxy-vitamin-d3
  25. https://pubs.acs.org/doi/10.1021/acs.jmedchem.9b00208
  26. https://www.sciencedirect.com/science/article/abs/pii/0003986179902261
  27. https://pmc.ncbi.nlm.nih.gov/articles/PMC4613797/
  28. https://pmc.ncbi.nlm.nih.gov/articles/PMC3089062/
  29. https://www.researchgate.net/publication/7611927_Synthesis_of_1a-Hydroxyvitamin_D_5_Using_a_Modified_Two_Wavelength_Photolysis_for_Vitamin_D_Formation
  30. https://academic.oup.com/jnci/article/89/3/212/2526685
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