Vitamin D3, derivative

Calcipotriol is a vitamin D3 derivative which is used as a topical agent in the treatment of psoriasis. Although not completely elucidated its mechanism of action seems to be based on inhibition of the proliferation and stimulation of the differentiation of epidermal keratinocytes. Adverse effects include irritation of the skin but also urticarial reactions. Calcipotriol has 100 fold less vitamin D activity as its active vitamin D3 metabolite calcitriol. However, calcipotriol in overdose can cause symptoms of hypercalcemia. 

Calcipotriene (Dovonex), a synthetic vitamin D3 derivative, is indicated for the treatment of moderate plaque psoriasis. Its mechanism of action is unknown, although it competes for calcitriol receptors on keratinocytes and normalizes differentiation. It also has a variety of immunomodulatory effects in the skin. Although the drug can cause local irritation, the most serious toxicities are hypercalciuria and hypercalcemia, which are usually reversible. 

Cholecalciferol is pure vitamin D3 derived from the ultraviolet conversion of 7-dehydrocholesterol to cholecalciferol. Ergocalciferol vitamin D2) is a sterol derived from yeast and fungal ergosterol. Calcitriol [Rocaltrol, 1,25-(0H)2D3] is the metabolically active vitamin D3 compound. Dihydrotachysterol is a synthetic compound that may act somewhat more quickly than either vitamin D2 or D3. 

Calcipotriene (Dovonex) Synthetic vitamin D3 derivative suppresses cell growth, causes local irritation, monitor for hypercalciuria and hypercalcemia... 

In a recent elegant synthetic application of this methodology, Vande-walle and co-workers have prepared some vitamin D3 derivatives.60 Scheme 6-VI shows a synthesis of 12-hydroxy vitamin D3 from 7-dehy-drocholesterol. The key feature of this route is the protection of the sensitive triene moiety as its Diels-Alder adduct with jV-phenyltriazoline-3,5-dione. 

Fucosterol (35), a sterol which is potentially available in large quantity from the harvest of kelp, has been used by Japanese chemists as an entry into the preparation of side chain hydroxylated vitamin D3 derivatives (120, 121, 181). The acetate of fucosterol (36) may be... 

Imazeki, I., Matsuzaki, J., Tsuji, K., Nishimura, T. 2006. Immunomodulating effect of vitamin D3 derivatives on type-1 cellular immunity. BiomedRes 27 1-9. 

A novel scheme to Vitamin D3 derivatives has been reported by Okamura and his co-workers. The key step in the sequence is the coupling of the cuprate... 

A steroid very closely related structurally to cholesterol is its 7 dehydro derivative 7 Dehydrocholesterol is formed by enzymatic oxidation of cholesterol and has a conju gated diene unit m its B ring 7 Dehydrocholesterol is present m the tissues of the skin where it is transformed to vitamin D3 by a sunlight induced photochemical reaction... 

Vitamin D3 (VD3) and retinoids synergistically inhibit the growth and progression of squamous cell carcinomas and actinic keratoses in chronically sun exposed skin. One reason for this synergism may be the direct influence of VD3 on the isomerization and the metabolism of RA. Here, VD3 inhibits the isomerization of 13-cis-RA to the more receptor active all-trans and 9-cis-isomers. Moreover, the VD3 derivative secocholestra-trien-l,3,24-triol (tacalcitol), used for the treatment of severe keratinizing disorders inhibits 4-hydroxylation of all-ri ans-RA. 

Vitamin D3 enters the skin microcirculation after formation and is bound to a specific globulin in the serum. It and vitamin D2 which is absorbed from the gut are subsequently metabolized to the 25-hydroxy derivative (25-OH-D) in the liver by an enzyme system which may or may not be regulated. The subsequent release of 25-OH-D from the liver is not well understood. There is evidence that it is secreted into the bile and subsequently reabsorbed by the intestine. The relative importance of this "enterohepatic" process and the release of this metabolite directly into the circulation from the liver is not known (26). 

An efficient synthetic route to (10Z)- and (10 )-19-lluoro-la,25-dihydroxy vitamin D3 has been developed (488). The key feature of this pathway is the introduction of a 19-fluoromethylene group to a (5 )-19-nor-10-oxo-vitamin D derivative. The 10-oxo compound 445 has been obtained via a 1,3-dipolar cycloaddition reaction of (5 )-la,25-dihydroxyvitamin D with in situ generated nitrile oxide, followed by ring cleavage of the formed isoxazoline moiety with molybdenum hexacarbonyl. Conversion of the keto group of (5 )-19-nor-10-oxo-vitamin D to the E and Z fluoromethylene group has been achieved via a two-step sequence, involving a reaction of lithiofluoromethyl phenyl sulfone, followed by the reductive de-sulfonylation of the u-lluoro-j3-hydroxysulfone. The dye-sensitized photoisomerization of the (5 )-19-fluorovitamin D affords the desired (5Z)-19-fluorovitamin D derivatives, (10Z)- and (10 )-19-fluoro-la,25-dihydroxy-vitamin D3. 

An efficient and high-yielding enzymatic protocol for regioselective alkoxycarbonylation of the diol precursor of lo ,25-dihydroxyvitamin D3 has been accomplished. The procedure provided a convenient synthesis of the A-ring vinyl carbonate derivative, which is a useful synthon of vitamin D3 analogues for pharmaceutical research. ... 

Vitamin D is commonly found in two forms, both derivatives of steroids. These are known as cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2). Cholecalciferol is formed directly from the steroid known as 7-dehydrocholesterol by the action of sunlight, or other source of ultraviolet (UV) light, in the skin of humans and other animals. When parents encourage their children to go out and play in the sun, there is good reason for doing so (but avoid sunburn). ... 

Recent studies describe the use of cyclic voltammetry in conjunction with controlled-potential coulometry to study the oxidative reaction mechanisms of benzofuran derivatives [115] and bamipine hydrochloride [116]. The use of fast-scan cyclic voltammetry and linear sweep voltammetry to study the reduction kinetic and thermodynamic parameters of cefazolin and cefmetazole has also been described [117]. Determinations of vitamins have been studied with voltammetric techniques, such as differential pulse voltammetry for vitamin D3 with a rotating glassy carbon electrode [118,119], and cyclic voltammetry and square-wave adsorptive stripping voltammetry for vitamin K3 (menadione) [120]. 

Vitamin D is represented by cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2), which are structurally similar secosteroids derived from the UV irradiation of provitamin D sterols. In vertebrates, vitamin D3 is produced in vivo by the action of sunlight on 7-dehydrocholesterol in the skin. Vitamin D2 is produced in plants, fungi, and yeasts by the irradiation of ergosterol. On irradiation, the provitamins are converted to previtamin D, which undergoes thermal transformation to vitamin D. 

Vitamin D3 is a precursor of the hormone 1,25-dihy-droxyvitamin D3. Vitamin D3 is essential for normal calcium and phosphorus metabolism. It is formed from 7-dehydrocholesterol by ultraviolet photolysis in the skin. Insufficient exposure to sunlight and absence of vitamin D3 in the diet leads to rickets, a condition characterized by weak, malformed bones. Vitamin D3 is inactive, but it is converted into an active compound by two hydroxylation reactions that occur in different organs. The first hydroxylation occurs in the liver, which produces 25-hydroxyvita-min D3, abbreviated 25(OH)D3 the second hydroxylation occurs in the kidney and gives rise to the active product 1,25-dihydroxy vitamin D3 24,25 (OH)2D3 (fig. 24.13). The hydroxylation at position 1 that occurs in the kidney is stimulated by parathyroid hormone (PTH), which is secreted from the parathyroid gland in response to low circulating levels of calcium. In the presence of adequate calcium, 25(OH)D3 is converted into an inactive metabolite, 24,25 (OH)2D3. The active derivative of vitamin D3 is considered a hormone because it is transported from the kidneys to target cells, where it binds to nuclear receptors that are analogous to those of typical steroid hormones. l,25(OH)2D3 stimulates calcium transport by intestinal cells and increases calcium uptake by osteoblasts (precursors of bone cells). 

Uptake of Ca2+ from the intestine is stimulated by vitamin D.447 Vitamin D3 is converted to the 25-hydroxy derivative in the liver (equation 11) by a two component mixed-function hydroxylase.448 The metabolically active 1,25-dihydroxy form is synthesized by further hydroxylation in the kidney. This latter stage involves the renal 25-hydroxyvitamin D3- 1-hydroxylase in a reaction which is controlled by Ca2+, parathyroid hormone and phosphate. This renal hydroxylase contains a flavoprotein, an iron-sulfur protein (with an Fe2S2 cluster) and cytochrome P-450.447... 

Vitamin D. Vitamin D is a steroidlike hormone that can be obtained from dietary sources or synthesized in the skin from cholesterol derivatives in the presence of ultraviolet light. Vitamin D produces several metabolites that are important in bone mineral homeostasis.27,31 In general, vitamin D derivatives such as 1,25 dihydroxyvitamin D3 increase serum calcium and phosphate levels by increasing intestinal calcium and phosphate absorption and by decreasing renal calcium and phosphate excretion.27,46... 

---