La,25-Dihydroxy-vitamin

A chiral nonracemic cyclic allyl iodide was shown to react with excess chromium(II) chloride and (4-methoxyphenylmethoxy)acetaldehyde to yield a single diastereomer, which was converted to la,25-dihydroxy vitamin D332. 

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. 

TF transcription factor, R receptor, Fur ferric uptake regulation protein, NF-kB nuclear factor-kB, AP-1 activator protein-1, Egr-1 early growth response-1, VDR la,25-dihydroxy-vitamin D3 receptor, RXR retinoid X receptor, PPARy peroxisome proliferator-activated receptor y NFAT nuclear factor of activated T-cells, HSF heat shock factor, p53 tumor suppressor p53, HIF-1 hypoxia inducible factor-1. ... 

Kleuser, B., Cuvillier, O. and Spiegel, S., 1998, la,25-Dihydroxy vitamin Dsinhibits... 

The active forms of the D vitamins are la,25-dihydroxy-vitamin Dj and 25-hydroxy-vitamin Dj. They are formed by enzymatic hydroxylation in the liver microsomes and then in the kidney mitochondria by a ferredoxin flavoprotein and cytochrome P-450. The 1,25-dihydroxy vitamin is then transported to the bone, intestine, and other target organs (kidneys, parathyroid gland). Consequently, it can be considered a hormone since it is produced in one organ but used elsewhere. It mobilizes calcium and phosphate and also influences the absorption of these ions in the intestine, thus promoting bone mineralization. The hormone is also active in relieving hypoparathyroidism and postmenopausal osteoporosis, which, for example, results in the brittle bones of elderly women. 

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... 

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. 

H9. Hedlund, T. E., Moffatt, K. A., and Miller, G. J., Stable expression of the nuclear vitamin D receptor in the human prostatic carcinoma cell line JCA-1 Evidence that the antiproliferative effects of la, 25-dihydroxy vitamin D3 are mediated through the genomic signalling pathway. Endocrinology 137, 1554-1561 (1996). 

Cycloaddition of 4-phenyl-3//-l,2,4-triazole-3,5(4//)-dione to provitamin D3 affords exclusively the product formed by addition to the least hindered a-face of the more reactive diene, the structure was determined by X-ray8. The diastereoselectivity appears to be determined by the steric effect of the rran.v-hydrindane system, although the mechanism has not been elucidated. The cycloaddition of 4-phenyl-3//-l,2,4-triazole-3,5(4//)-dione was exploited to temporarily protect the diene group in the syntheses of la-hydroxy vitamin D3 7 a(X = H)8,9 and la,25-dihydroxy vitamin D3 7b (X = OH, starting from 25-hydroxy provitamin D3)10. Complete stereocontrol was observed in the cycloreversion step. For related cycloadditions to vitamin D3 see Section 7.2,10.3.4. 

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. 

Ozone on silica gel introduces a 25-hydroxy-substituent into suitable compounds with a cholestane side-chain. By using the la,3/8-diacetoxy-6/8,7a-dibromo-derivative (383), prepared from the known 6-ene, the 25-hydroxylated compound was obtained as the only product (11% conversion). Trifluoroacetylation followed by dehydrobromination afforded the 5,7-diene (385), which was transformed into la,25-dihydroxy-vitamin D3 by the usual method. 

The cyclohexyl fragment of FK-506 (Scheme 6.62) [85] and la,25-dihydroxy-Vitamin D3 Ring A synthon (Scheme 6.63) [87] were readily accessible by trans- and cis-selective cychzation, respectively. 

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... 

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]. 

In the catalyzed inverse electron demand Diels-Alder reaction of dienophile 1 with diene 2, a d.r. of 98 2 is observed. The adduct 3 is converted into the key synthon of la,25-dihydroxy-vitamin D382. 

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