1,25-Dihydroxyvitamin synthesis

PTH has a dual effect on bone cells, depending on the temporal mode of administration given intermittently, PTH stimulates osteoblast activity and leads to substantial increases in bone density. In contrast, when given (or secreted) continuously, PTH stimulates osteoclast-mediated bone resorption and suppresses osteoblast activity. Further to its direct effects on bone cells, PTH also enhances renal calcium re-absorption and phosphate clearance, as well as renal synthesis of 1,25-dihydroxy vitamin D. Both PTH and 1,25-dihydroxyvitamin D act synergistically on bone to increase serum calcium levels and are closely involved in the regulation of the calcium/phosphate balance. The anabolic effects of PTH on osteoblasts are probably both direct and indirect via growth factors such as IGF-1 and TGF 3. The multiple signal transduction... 

Calcitriol, 1,25-dihydroxyvitamin D3, directly suppresses PTH synthesis and secretion and upregulates vitamin D receptors, which ultimately may reduce parathyroid hyperplasia. The dose depends on the stage of CKD and type of dialysis (Table 76-4). 

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. ... 

Parathyroid hormone is a single-chain polypeptide of 84 amino acids which is produced in the parathyroid glands. It increases serum calcium and decreases serum phosphate. In bone it promotes resorption of calcium. It indirectly increases osteoclastic activity by promoting the action of osteoblasts. It has been shown that in low doses PTH may even increase bone formation without stimulating bone resorption. In the kidney PTH increases resorption of calcium and it increases excretion of phosphate. An other important activity in the kidney is the enhanced synthesis of 1,25-dihydroxyvitamin D. An increased serum calcium level inhibits PTH secretion and increased serum phosphate decreases free serum calcium and thus stimulates PTH secretion. 

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. 

Frohlich, L. and Torsten, L. (2004) Simple and diastereoselective synthesis of an A-ring precursor of dihydroxyvitamin D3 (caldtriol) by photooxygenation. Syrdett, (15), 2725-2727. 

Franceschi RT, Romano PR, and Park KY (1988) Regulation of type I collagen synthesis by 1,25-dihydroxyvitamin D3 in human osteosarcoma cells. Journal of Biological Chemistry 263,18938-45. 

Rowe DW and Kream BE (1982) Regulation of collagen synthesis in fetal rat calvaria hy 1,25-dihydroxyvitamin D3. Journal of Biological Chemistry 257, 8009-15. 

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]. 

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. 

Scheme 3-18 The key step of an elegant synthesis of Ioi,25-dihydroxyvitamin D3 (calcitriol) 1170].

In 1971, Salen reported (12) that the rare inheirted lipid storage disease, cerebrotendinoux xanthomatosis (CTX), was associated with defective bile acid synthesis. The major and prominent clinical features in CTX syndrome were tendon xanthomas, juvenille cataracts, dementia, pyramidal paresis, cerebellar ataxis, abnormal electroencephalogram (EEC), and cerebral computed tomographic (CT) scans, premature atherosclerosis, pulmonary dysfunction and osteoporosis. Low serum levels of 25-hydroxyvitamin D3 and 24,25-dihydroxyvitamin D3 were also detected in these patients in association with osteoporosis and frequent bone fractures (13,14). The disease is inherited as an autosomal recessive trait, but is usually detected in adults when cholesterol and cholestanol have accumulated over many years (13-16). Major biochemical... 

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). 

Measurement of BAP may be misleading in patients with fiver disease, severe osteomalacia, or increased concentrations of 1,25(0H)2D. bap maybe misleading in liver disease because of the cross-reactivity of current methods with fiver ALP. In severe osteomalacia, BAP maybe markedly increased without an increase in bone mineralization because of a mineralizing defect. Because 1,25-dihydroxyvitamin D regulates the synthesis of BAP and osteocalcin, both of these markers may be misleading in patients treated with calcitriol and in patients with abnormal concentrations of this hormone. 

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. 

Reichel, H. et al. (1987) la, 25-Dihydroxyvitamin Dj inhibits Y-interferon synthesis by normal human peripheral blood lymphocytes. 

Examples of endogenous biotransformation reactions catalyzed by cytochrome P450 electron transport systems include the synthesis of steroid hormones from cholesterol (Chapter 12) and the conversion of vitamin D3 to its biologically active form 1,25-dihydroxyvitamin D3. 

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