Hydroxycholesterols

In studies which may have a bearing on the preparation of other functionalized side chain analogs, Trost and Verheoven have shown 

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). 

Fucosterol (35), a sterol which is potentially available in large quantity from the harvest of kelp, has been used by Japanese chemists as an entry into the preparation of side chain hydroxylated vitamin D3 derivatives (120, 121, 181). The acetate of fucosterol (36) may be 

It would seem that ergosterol, provitamin D2 (la), would serve as an ideal precursor for side chain oxygenated vitamin D derivatives because of its ready availability from yeast and its preexisting 5,7-diene system. However, the reactivity of the diene moiety in its free or protected form (vide infra) has complicated the selective manipulation of the side chain. Eyley and Williams have studied the reactions of the aldehyde (43) obtained in modest yield by selective ozonization of 

From the commercial point of view, the cheap and readily available plant sterol, stigmasterol ( ), presently appears to be the most desirable starting material for the preparation of vitamin D metabolites. Since the two double bonds of stigmasterol exhibit nearly equal reactivity toward oxidizing agents it has been necessary to first protect the 5,6-double 

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The toxic effect of 7-oxysterols, 25- and 27-hydroxycholesterols and their involvement in LDL cytotoxicity have been extensively studied on the different vascular cell types (Lizard et al, 1999 Aupeix et al, 1995 Clare et al, 1995 Ramasamy et al, 1992). 7a and 7p-hydroxycholesterols, 7-ketocholesterol, 25 and 27-hydroxycholesterol induce apoptosis (Brown and Jessup, 1999 Lizard et al, 1999, 1998 Zhang et al, 1997 Hughes et al, 1994). 7p-hydroperoxycholesterol is one of the most toxic Oxysterols present in oxidized LDL (Brown and Jessup, 1999 Colles et al, 1996). 25-hydroxycholesterol, though less active (Aupeix et al 1995), is able to trigger a cytochrome c release and subsequent caspase activation in CHO cells, but also calcium inaease in relation with apoptosis (Rusinol et al, 2000). 

Martin C, Bean R, Rose K, Habib F, Seek J. 2001. cyp7bl catalyses the 7alpha-hydroxylation ofdehydroepiandroster-one and 25-hydroxycholesterol in rat prostate. Biochem J... 

A full account of the syntheses of the four isomeric 20,22-epoxycholesterols is accompanied by two similar reports. Pregnenolone has been converted by two independent routes into 25-oxo-27-norcholesteryl acetate. Both routes employed the highly stereoselective platinium-catalysed hydrogenation of the 20,22-double bond which in one case was shown to have the E-configuration. Three additional syntheses of 25-hydroxycholesterol have been reported. The 6/3-methoxy-3a,5a-cyclo-20-carboxaldehyde (261), derived from stig-masterol, was converted into the diene (262) " or the dichloro-olefin (263) and thence into 25-hydroxycholesterol as indicated in Scheme 10. Alternatively the side-chain of the bromo-derivative (264) was extended as indicated in Scheme 2 2 186... 

In contrast to these results, 25-hydroxycholesterol (and also, 20-hy-droxycholesterol, 7-ketocholesterol, and diosgenin) in aortic, smooth-muscle cells effectively blocks the incorporation of acetate into lipid-linked oligosaccharides (and, also, into cholesterol7). Thus, less of the lipid-linked oligosaccharides were available for glycosylation of proteins. In harmony with the presumed, inhibitory mechanism was the observation that incorporation of mevalonate into lipid-linked oligosaccharides was not inhibited, and that mevalonate itself (the product formed by HMG-CoA reductase from HMG-CoA and NADPH) could reverse the inhibition of glycosylation of protein (see Scheme 1). 

Purification of cholesterol through the dibromide completely eliminates cholestanol, 7-dehydrocholesterol, and latho-sterol (A7-cholestenol). The first crop of material from methanol-ether is also free from cerebrosterol (24-hydroxycholesterol) and 25-hydroxycholesterol, a product of autoxidation present in cholesterol that has been stored in the crystalline state for a few years with access to air. When material of highest purity is desired, only first-crop dibromide should be employed, since de-bromination of second-crop material gives sterol melting at 146-147° and giving a positive Beilstein test. 

Cox, D.C., K. Comai, and A.L. Goldstein. 1988. Effects of cholesterol and 25-hydroxycholesterol on smooth muscle cell and endothelial cell growth. Lipids 23 85. 

Lange, Y., Ye, J., Strebel, F. 1995. Movement of 25-hydroxycholesterol from the plasma membrane to the rough endoplasmic reticulum in cultured hepatoma cells. J. Lipid Res. 36, 1092-1097. 

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. 

The previously described (24S)-24,25-epoxycholesteryl benzoate has been reduced with lithium aluminium hydride-aluminium chloride to give a chromato-graphically separable mixture of 25-hydroxycholesterol (55%) and (24S)-24-hydroxycholesterol (273),133 the configuration of which was determined by the modified Horeau method.135 It is interesting to note that cerebrosterol isolated from brain is (24S)-24-hydroxycholesterol whereas natural 24,25-dihydroxy-vitamin D3... 

Rearrangement of dienols. Dienols of the type 2 bearing methylthio or phenylthio substituents are readily available by sequentia, condensation of 1-(methylthio)-l-(tri-methylsilyl)-2-propene (1)- with two ketones (equation 1). On treatment with NiCl, [Ni(OAc), Ni(acac)2, and PdCU are less useful] in aqueous t-BuOH, 2 rearranges to the dienol 3. This rearrangement was used in a synthesis ol (20R)-25-hydroxycholesterol (4) from pregnenolone to transpose a Cjo-hydroxy group to the Cj-position (equation II). 

Addition of alkenylzirconium (51) to steroid-derived allylpalladium (52), followed by hydrogenation and hydrolysis, gives 25-hydroxycholesterol in 66% overall yield from (52 Scheme 15). Finally,... 

Several COPs have been identified as having cytotoxic, angiotoxic, carcinogenic, and mutagenic bioactivities (280, 281), all or some of which may play a role in the initiation or proliferation of atherosclerotic plaque. Specifically, 25-hydroxycholesterol and cholestane-36,5a,66-triol are particularly toxic to cultured rabbit aortic smooth muscle cells (278). The 25-hydroxycholesterol... 

For the synthesis of oxiranes with more complex structures, the peracid method is combined with other epoxidation procedures examples are the syntheses of ( )-crotoxirane, ( )-epicrotoxirane, and ( )-isocrotoxirane ° or the preparation of cis-trioxatris-(a)homotropylidene. o-Sulfoperbenzoic acid has been used for the stereoselective epoxidation of cholesterol. The selective epoxidation of cholest-5-en-3-one too has been examined. In the synthesis of 25-hydroxycholesterol selective epoxidation occurs on and 26 is formed. The epoxidation of olefin propellanes 27 and 28 can be achieved with MCPBA. As a consequence of the secondary orbital interaction, syn-attack is more marked in the case of 28. ° Epoxypropelladiene can be synthesized in accordance with Eq. 12. ... 

Figure 9. The products of free radical autoxidation of cholesterol (1), 25-hydroxycholesterol ...

A fourth companion, cerebrosterol, or 25-hydroxycholesterol, is easily eliminated by crystallization from alcohol. 

Fig-1 Structures of naringenin (flavanone, 1), naringin (flavanone O-glycoside, 2) and rutin (flavonol O-glycoside, 3), ketoconazole (4), 7/3-hydroxycholesterol (5) and 25-hydroxycholesterol (6), resveratrol (7) and etoposide (8, VP-16)... 

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