La,247?-Dihydroxyvitamin

Fig. 9. Human disease states in which vitamin D has been impHcated. D3 = vitamin D DHD = la, 25 — dihydroxyvitamin D ...

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. 

Schmiedlin-Ren P, Thummel KE, Fisher JM, Paine MF, Lown KS, Watkins PB (1997) Expression of enzymatically active CYP3A4 by Caco-2 cells grown on extracellular matrix-coated permeable supports in the presence of la-25-dihydroxyvitamin D3. Mol Pharmacol 51 741-754. 

Selective Alkoxycarbonylation of la,25-Dihydroxyvitamin D3 Diol Precursor with Candida antarctica Lipase B... 

Vitamin D3 is transported toward the liver where it undergoes hydroxylation at C-25 to la,25-dihydroxyvitamin D3 (calcitriol Figure 4.11). In the kidney, it undergoes... 

A second major vitamin D metabolite is 24R,25-dihydroxyvitamin D3, a compound that circulates in the blood at a concentration 10 times higher than that of the 1,25-isomer.a b However, no biological function has been discovered, and like a series of other polar metabolites (>30) it is probably on a pathway of inactivation and degradation of vitamin D. la,25-Dihydroxyvitamin D is also hydroxylated... 

The hormonally active la,25-dihydroxyvitamin D is distributed through the bloodstream to all parts of the body. It is taken up rapidly by nuclei of cells of the intestinal lining where it binds to a 55-kDa receptor protein. In response, the cells synthesize calbindins (Chapter 6), Ca2+-binding proteins which facilitate the uptake of calcium ions by the body.1 v (see also Fig. 6-7). 

Recently, much effort has been directed to the synthesis of analogs of the biologically active form of vitamin D3, la,25-dihydroxyvitamin D3 [la,25(OH)2D3] as an important new field in medicinal chemistry [50], As a new and efficient route to this class of compounds, the symmetry -assisted enantiospecific synthesis of the A-ring of the vitamin D-hybrid analogs, 19-nor-22-oxa-la,25(OH)2D3 was reported (Scheme 8C.20) [51]. It should be noted that any gem-dialkyl substituents is not necessary to attain a high level of enantioselectivity. 

Recently, Palmer et al., working with human colon cancer cell lines, reported dramatic up-regulation of kallikreins 6 and 10 by la, 25-dihydroxyvitamin D3 [158]. This finding raises the possibility that some kallikreins could be regulated by a multitude of nuclear receptors. 

Initially, 25-OH-D3 was considered to be the main biologically active metabolite of vitamin D. But soon it was discovered that physiological concentrations of 25-0H-D3, like vitamin D3, are incapable of stimulating either intestinal calcium transport or bone calcium jnobilization (108-110). Earlier work (111,112) with [la- H] vitamin D3 had shown that one of the unknown metabolites had lost its tritium from the C-l position. Fraser and Kodicek (113) established that this active metabolite is 1-oxygenated 25-OH-D3 and that it was produced in the kidney. A short time later Lawson et al. (114) identified this metabolite to be la, 25-dihydroxyvitamin D3 (1,25-(0H)2D3) which was confirmed by other investigators (115,116). 

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 ... 

Schroder and co-workers (Schroder etal., 1999,2000) studied PolyP metabolism in bone tissues and osteblast cultures. They revealed that PolyP metabolism in human osteoblasts was modulated by stimulators of osteoblast proliferation and differentiation (Leyhausen et al., 1998). A combined treatment of the cells with dexamethasone, ft-glycerophosphate, epidermal growth factor (EGF), and ascorbic acid resulted in a dramatic decrease in PolyP content. This decrease is caused mainly by a decrease in the amount of soluble long-chain PolyPs. The amount of this PolyP fraction, but not the amount of insoluble long-chain PolyPs, further decreases after additional treatment of the cells with la, 25-dihydroxy vitamin D3. The decrease in PolyP content during treatment with dexamethasone, ft-glycerophosphate, EGF and ascorbic acid is accompanied by a decrease in exopolyphosphatase activity. However, additional treatment with la, 25-dihydroxyvitamin D3 results in a significant increase of the enzyme activity. Therefore, it is reasonable to assume that PolyP... 

Obeid, L.M., Linardic, C.M., Karolak, L.A., and Hannun, Y.A., 1993, Programmed cell death induced by ceramide, Science 259 1769-1771 Okazaki, T., Bell, R.M., and Hannun, Y.A., 1989, Sphingomyelin turnover induced by vitamin D3 in HL-60 cells. Role in cell differentiation. J. Biol. Chem. 264 19076-19080 Okazaki, T., Bielawska, A., Bell, R.M., and Hannun, Y. A., 1990, Role of ceramide as a lipid mediator of la, 25-dihydroxyvitamin D3-induced HL-60 cell differentiation. J. Biol. Chem. 265 15823-15831... 

Kleuser, B., Cuvillier, O., and Spiegel, S., 1998, la,25-dihydroxyvitamin D3 inhibits programmed cell death in HL-60 cells by activation of sphingosine kinase. Cancer Res. 

In the context of the synthesis of a precursor of la,25-dihydroxyvitamin D3, Posner and Kinter treated allylic alcohol (115) with ethyl orthoacetate in a sealed tube. - The resultant 7,8-unsaturated ester... 

Posner and Kinter have demonstrated MAD-promoted highly stereoselective [4 + 2] cycloaddition under mild conditions in the asymmetric total synthesis of an A-ring precursor 171 to hormonally active la,25-dihydroxyvitamin D3 [172]. Reaction of a pyrone sulfone 168 and an enantiomerically pure vinyl ether 169 under the influence of MAD in toluene-CH2Cl2 at -45 °C for 12 h afforded cycloadduct 170 in 93 % isolated yield as a 98 2 ratio of the endo diastereomers. From 170, the synthesis of 171 required 13 steps and proceeded in 34.6 % overall yield as indicated in Sch. 133. 

The synthetic utility of the vinylic sulfide and selenide approach is exemplified by the synthesis of enantio-pure (i )-(-)-ipsdienol, an insect aggregation pheromone (Sch. 13) [54], Kabat and Uskokovic have demonstrated the asymmetric catalytic synthesis of la,25-dihydroxyvitamin D3 (la,25(OH)2D3) A-ring synthon by means of a glyoxylate-ene reaction catalyzed by BINOL-Ti complex (1) (Sch. 14) [55]. 

In a further study, serum concentrations of 25-hydroxyvitamin D, 24,25-dihydroxyvitamin D and la,25-dihydroxyvitamin D were measured in 10 Cd-exposed subjects and 5 non-exposed subjects [100]. The Cd-exposed subjects were divided into two groups according to serum la,25-dihydroxyvitamin D levels. No significant differences for 25-hydroxyvitamin D were found between the Cd-exposed group with low or normal serum la,25-dihydroxyvitamin D and the... 

Firstly, Cd causes renal damage with effects principally on renal tubular cells, i.e. the site of la,25-dihy-droxyvifamin D synfhesis resulfing in an infrinsic vitamin D deficiency. This will impair the gastrointestinal absorption of calcium, reduce the calcium incorporation in bone and ultimately result in the development of osteomalacia. It is well known that la,25-dihydroxyvi-tamin D is the biologically active metabolite of vitamin D. As there is a sequential relationship between the synthesis of la,25-dihydroxyvitamin D in the kidney and cyclic-adenosine monophosphate, adenylcyclase, parathyroid hormone, a direct interference of Cd with any of these steps cannot be excluded. 

Nogawa K,Tsuritanl I, KidoT, Honda R, Yamada Y, Ishizaki M. Mechanism for bone disease found In Inhabitants environmentally exposed to cadmium decreased serum la,25-dihydroxyvitamin D level. Int Arch Occup Environ Health 1987 59 21-30. 

Reaction of sulfone pyrone 164c with enantiomerically pure vinyl ether (5)-355b in the presence of a Lewis add such as [4-Me-2,6-(r-Bu)2QH20]2-MeAl at -45°C in 1 1 toluene/methylene chloride gives the cycloadduct 356b in 93% yield as a 98 2 ratio of the endo diastereomers. This reaction is applied to the synthesis of la,25-dihydroxyvitamin D3 (354b) (90JOC3967). 

Durk MR, Chan GN, Campos CR, Peart JC, Chow EC, Lee E et al (2012) la,25-Dihydroxyvitamin D3-liganded vitamin D receptor increases expression and transport activity of P-glycoprotein in isolated rat brain capillaries and human and rat brain microves-sel endothelial cells. J Neurochem 123 944-953... 

Methyl- and ethylmagnesium halides were reacted with an ethoxycarbonyl moiety, affording the corresponding tertiary alcohol, in the solid-supported synthesis of 19-raor-la,25-dihydroxyvitamin Ds and its derivatives. PS-DES-Cl [101] resin was employed. Cleavage was achieved with aq. H F. 

Ando, K., Koike, E, Kondo, E, and Takayama, H., An improved synthesis of 24,24-difluoro-la,25-dihydroxyvitamin Dj from readily available vitamin Dj, Chem. Pharm. Bull., 43, 189, 1995. 

---