Dihydroxy vitamin synthesis

The yield of the fkst chemical synthesis of 1,25-dihydroxy-vitamin was <0.005% (124). A key kitermediate compound was 1,25-dihydroxy-cholesterol (109,125—130). 

The chemical syntheses of l,24(R),25-trihydroxy-vitamiQ [56142-94-0] and l,24(3),25-trihydroxy-vitamiQ D [56142-95-1] were reported (131,132) ki 1975. The chemical synthesis of 25,26-dihydroxy-vitamin [29261 -12-9] has also been described, and it has been determined that the biologically occurring epimer is 25(R),26-dihydroxy-vitamin (117,133—135). The 23,25-dihydroxy-24-oxo metabohte has been isolated (136) as well. 1 a-Hydroxycalcitroic acid (l-hydroxy-24-nor-9,10-secochola-5,7-10(19)-ttien-23-oic acid) [71204-89-2], 25-hydroxy-26,23-lactone vitamin [71203-34-6],... 

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... 

OH)2 D3 or dihydroxy vitamin D3) occurs in mitochondria of the proximal tubules. The pathway of dihydroxy vitamin D3 synthesis is shown in Figure 8.11. 

Figure 8.12 Feedback control of dihydroxy vitamin D3 synthesis by ionized calcium...

Attempts to demonstrate 25-hydroxy-vitamin D3-l-hydroxylase activity in vitro with rat kidney homogenates have been unsuccessful, although chick kidney preparations exhibit such activity. A heat-labile and very potent inhibitor of the hydroxylase has now been found in the rat preparation 322 all fractions of the kidney homogenate contained the factor, but the microsomes were the richest source, and they released the inhibitor during incubation. A similar inhibitor is also present in rat intestine and serum and in pig kidney, and it may well play a regulatory role in the synthesis of 1,25-dihydroxy-vitamin D3.323 Direct spectroscopic and inhibitory evidence for the presence of cytochrome P450 in kidney mitochondria and of its... 

Recent findings show that vitamin D3 must be hydroxylated at C-25 by the liver and then at C-la by the kidney to 1 a,25-dihydroxy-vitamin D3 before it can induce calcium transport. It is therefore not surprising to find several reports on the synthesis of both the la,25-dihydroxy-vitamin and la,25-hydroxycholesterol. 

CH(Me)(CH2)2CH=CMe2 and CH(Me)(CH2)3C(Me)=CH2. The 25-hydroxy-group was restored at the end of the synthesis. Successive acetylation, bromination, dehydrobromination, saponification, and irradiation when applied to la,25-dihydroxycholesterol convert it either into la,25-dihydroxy-previtamin D3128 or into a la,25-dihydroxy-vitamin D3,129 depending on reaction conditions. 

Basic research on the synthesis of analogs of the biologically active form of vitamin D3, la,25-dihydroxy vitamin D3 (la,25(OH)2D3) has led to the development of an important new field in medicinal chemistry [84]. We have also reported symmetry assisted enantiospecific synthesis of the A-ring of the vitamin D hybrid analogs, 19-nor-22-oxa-la,25(OH)2D3 (Sch. 29) [85], It should be noted here that extremely high 1,3-frans selectivity was achieved by combining the (f )-BINOL-Ti catalyst and the (i )-ene substrate without geminal disubstitution. 

Stereoselective samarium-based Simmons-Smith cyclopropanation of cyclopentyl allylic alcohols is the key step in the synthesis of the precursor of 1,25-dihydroxy vitamin The... 

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

Stereoselective samarium-based Simmons-Smith cyclopropanation of cyclopentyl allylic alcohols is the key step in the synthesis of the precursor of 1,25-dihydroxy vitamin D3.128 The desired chirality was generated in one case under the influence of the two stereogenic centers on the (R,/ )-butane-2,3-diol acetal 121 and in the other case was directed entirely by the allylic hydroxy group of 122. 

The vitamin D receptor (VDR/NR1I1) is a member of the superfamily of steroid hormone receptors. It regulates calcium homeostasis, cell proliferation, and differentiation, and exerts immunomodulatory and antimicrobial functions [119]. VDR binds to and mediates the calcemic effects of calcitriol (la,25-dihydroxy vitamin D3) after forming an heterodimer with RXR. la,25-dihydroxyvitamin D3 negatively regulates its own synthesis by repressing the 25-hydroxyvitamin D3 la-hydroxylase (CYP27B1) in a cell-type selective event that involves different combinations of multiple VDR response elements [120, 121]. 

Anderson, P. H., P. D. O Longhlin, B. K. May, and H. A. Morris. 2004. Determinants of crr-cnlatmg 1,25-dihydroxy vitamin D3 levels The role of renal synthesis and catabolism of vitamin D. Journal of Steroid Biochemistry and Molecular Biology 89-90 111-113. 

Its structure was quickly confirmed by chemical synthesis which led to the preparation of radioactive 25-OH-D3 ° Using this preparation it was then possible to show that it, like its vitamin D precursor was rapidly metabolized further and appeared in the target tissues of intestine and bone before those tissues responded by increasing intestinal calcium absorption and the mobilization of calcium from bone In 1971 the most potent and hormonal form of vitamin D was isolated in pure form from chick small intestine and identified as 1,25-dihydroxyvitamin D3 (1,25-(0H)2D3) Its structure was then quickly confirmed by chemical synthesis proving its structure to be la25-dihydroxyvitamin D3 (la,25-(OH)2D3) . This conclusion was finally supported by the synthesis of the epimer ip,25-dihydroxy-vitamin D3 (l/i,25-(OH)2D3) and the demonstration that the natural product was identical with la,25-(OH)2D3 ... 

---