La,25-Dihydroxycholecalciferol

The vitamin D3 metabolite la,25-dihydroxycholecalciferol is a lifesaving drug in treatment of defective bone formation due to renal failure. Retrosynthetic analysis (E.G. Baggjolint, 1982) revealed the obvious precursors shown below, a (2-cyclohexylideneethyl)diphenylphosphine oxide (A) and an octahydro-4f/-inden-4-one (B), to be connected in a Wittig-Homer reaction (cf. section 1.5). 

In addition to being involved in the formation of urine, the kidney acts as an endocrine organ secreting renin, erythropoietin, prostaglandins (qv), and kinins it is also capable of synthesizing substances such as la,25-dihydroxycholecalciferol [32222-06-3] One of the principal functions of the... 

In the human body, cholecalciferol and ergocalciferol undergo two metabolic transformations to yield the active vitamin D molecule. These are additions of hydroxyl groups, first in the liver to produce 25-hydroxyvitamin D and then in the kidney. The final product has the unwieldy name la, 25-dihydroxycholecalciferol, and is more commonly known by its simpler name 1,25-dihydroxy vitamin D or, even more simply, l,25(OH)2D. 

In the skin, cholesterol is converted to 7-dehydrocholes-terol by desaturation of the 9,10-carbon bond and ultraviolet light breaks this bond to produce cholecalciferol (Figure 15.12). The cholecalciferol is transported via the bloodstream to the liver where the first step in the activation of the hormone occurs, namely hydroxylation by a monooxygenase to produce 25-hydroxy cholecalciferol, which is transported to the kidney where a further hydroxylation takes place at the 1-position to produce la,25-dihydroxycholecalciferol, which is the active form of the hormone (Figure 15.13). 

Chemical Name 9,10-Secocholesta-5,7,10(19)-triene-l,3,25-triol Common Name la,25-Dihydroxycholecalciferol la,25-Dihydroxyvitamin D3 Structural Formula ... 

Subsequently there was introduced a la-hydroxylated form (la-hydroxycholecalciferol) alfacalcidol (One-Alpha), that requires only hepatic hydroxylation to become the highly active la-25-dihydroxycholecalciferol (calcitriol). Alfacalcidol (and of course calcitriol) is therefore effective in renal failure since the defective renal hydroxylation stage is bypassed. Its extraordinary potency and efficacy is indicated by the usual adult maintenance dose, often only 0.25-1 micrograms/d. 

Parathyroid hormone acts chiefly on kidney increasing renal tubular resorption and bone resorption of calcium it increases calcium absorption from the gut, indirectly, by stimulating the renal synthesis of la-25-dihydroxycholecalciferol (see Vitamin D). It increases the rate of bone remodelling (mineral and collagen) and osteocyte activity with, at high doses, an overall balance in favour of resorption (osteoclast activity) with a rise in plasma calcium con-... 

Calcitriol (la,25-dihydroxycholecalciferol, vitamin D3, 105) (O Scheme 41) is involved in calcium metabolism. Glycosides of this compound occur in plants [200,201] and also as metabolites in mammal organisms. -Glucopyranosides of 105 linked to the C-1, C-3, or C-25 hydroxyfunctions were tested in vivo (rats) and compared with the aglycon. These glycosides occur as potential sources of vitamin D in plants, e. g., Solanum malacoxylon [200] where... 

Vitamin D occurs in a number of sterol forms, such as vitamin D3 - cholecalciferol - a natural form in foods and made in the skin by the action of UV, and vitamin D2 -ergocalciferol - which is formed in plants by the action of sunlight. These forms are 25-hydroxylated in the kidney, and then la-hydroxylated in the kidney (under the control of parathormone), to make the most active form. This is available as calcitriol (la,25-dihydroxycholecalciferol). Vitamin D facilitates the absorption of calcium and, to a lesser extent, phosphorus from the intestine and promotes deposition into the bones. A deficiency of vitamin D, therefore, results in bone deficiency disorders, e.g. rickets in children. Good food sources include eggs, milk and cheese. 

Vitamin D Analogues - A patent covering the photochemical conversion of the diene (112) into the triene (113) within what is called a microreactor has been published. The microreactor system is a zeolite with the appropriate size of the cavity to provide stereochemical control of the reaction. The use of the 2,7-dimethyl-3,6-diazacyclohepta-1,6-diene tetrafluoroborate/biphenyl filter solution has allowed the double wavelength irradiation (290-300 nm and X. > 330 nm) of procalcitriol as a route to la,25-dihydroxycholecalciferol. A study of the control that can be exercised upon the reaction by changes in temperature was carried out. The results of a study of the influence of intensity on the picosecond laser irradiation of provitamin D have been published. Other research has been aimed at the examination of the photochemical behaviour of previtamin 03. ... 

Oxidation of la-hydroxycholecalciferol and la,25-dihydroxycholecalciferol with Mn02 gave the corresponding 1 -oxo-previtamins which could be reduced with LiAlH4 at —25 °C in each case to give a mixture of la-hydroxy- and IjS-hydroxy-previtamins in which the IjS-epimers (285) and (286) predominated. Thermal equilibration allowed the isolation of the 1/3-hydroxy-cholecalciferol and l/ ,25-dihydroxycholecalciferol. A similar independent synthesis of 1/3-hydroxycholecalciferol employed NaBH4 for the reduction... 

Nomenclature. Vitamin D all steroids with chole-calciferol-like biological activity cholecalciferol (vitamin D3) 25-hydroxycholecalciferol (calcidiol) la,25-dihydroxycholecalciferol (calcitriol). 

The bile acid derivative, 3P-acetoxychol-5-en-24-oic acid (32), has been converted in two steps in high yield to 25-hydroxycholesterol (80). The homocholenic acid derivative (33) prepared by a photochemical Wolff rearrangement in this transformation served as a key early intermediate in the first chemical synthesis of la,25-dihydroxycholecalciferol (171). Lithocholic acid, likewise, has been converted to an intermediate (16) used for the preparation of the dihydroxyvitamin (35). Hyodeoxy-cholic acid (34) also shows promise of being a desirable starting material for 25-hydroxycholesterol (132). 

Brumbaugh, P. F., and Haussler, M. P., 1974, la,25-Dihydroxycholecalciferol receptors in intestine. II. Temperature-dependent transfer of the hormone to chromatin via a specific cytosol receptor, J. Biol. Ghent. 249 1258. 

Reichenbacher, M., Gliesing, S., Lange, C., Gonschlor, M., and Schonecker, B., Bin effecktives Verfahren zur Herstellung von la,25-Dihydroxycholecalciferol (Caldtriol) aus la,3p,25-Trihy-droxy-cholesta-5,7-dien (Procalcitriol),/. Prafct. Chem., 338, 634-641,1996. 

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