Cholesterol analogues

Shrivastava S, Haidar S, Gimpl G, Chattopadhyay A (2009) Orientation and dynamics of a novel fluorescent cholesterol analogue in membranes of varying phase. J Phys Chem B 113(13) 4475 1481... 

P NMR study of the interaction of nucleotide derivatives with membranes was reported by Bunge et al.102 The authors have used oligonucleotides that are modified by covalent attachment of the cholesterol analogue cholesteryl tri(ethylene glycol) (cholesteryl-TEG) and spontaneously incorporate into lipid membranes. The influence of cholesteryl-TEG on the lipid membrane compared to that of cholesterol within bilayer structure is shown in Figure 26. 

The nitroxide (33) closely resembles cholesterol in its physical and biological properties, and has been used as a spin-labelled analogue of cholesterol to investigate cholesterol-protein interactions in human high-density lipoprotein.146 The fluorescent cholesterol analogue A-(7-nitrobenz-2-oxa-l,3-diazole)-22-amino-23, 24-dinorchol-5-en-3p-ol (34) has been used as a substrate for lecithin cholesterol... 

Drew, J., Letellier, M., Morand, P., and Szabo, A.G.. Synthesis from pregnenolone of fluorescent cholesterol analogue probes with conjugated unsaturation in the side chain, J. Org. Chem.. 51, 4047,... 

Cytochrome P-450gf.p The demonstration of isozyme selectivity and the availability of structure-activity data has triggered efforts to construct irreversible inhibitors for biosynthetic cytochrome P-450 isozymes. Two types of mechanism-based inhibitors have been reported for cytochrome P-ASOg, the adrenal enzyme that oxidizes cholesterol to pregnenolone,1 3,104 cholesterol analogue ( ) with a triple bond between carbons 22 and 23 of the sidechain (the 20,22-bond is that which is normally cleaved) inactivates the enzyme by a catalysis-dependent mechanism.Replacement of carbon 24 and the attached sidechain carbons with a trimethylsilyl group (5 ) also results in inactivation of the enz3rme.l0 ... 

Figure 8 (a) Binding of cholesterol to cholesterol-imprinted and control polymers, from a 2 mM solution of cholesterol in hexane, as a function of polymer concentration, (b) Binding of cholesterol and various cholesterol analogues (2 mM) to the cholesterol-imprinted polymer, prepared by the sacrificial spacer method. Reprinted with permission from Journal of the American Chemical Society. Copyright 1995 American Chemical Society (Ref. 10). 

The cis P-lactams 57 are shown to act as cholesterol absorption inhibitors <96BMCL1947> and 58, an analogue of the dipeptide Phe-Gly methyl ester, is a protease inhibitor <96BMCL983>. A straightforward synthesis of proclavaminic acid 59, a biosynthetic precursor of clavulanic acid, is reported <96TA2277>. 

On the other hand, in the synthesis of cholesterol (30) by Woodward and CO workers [10] the less stable fran -configuration between rings C and D is attained through a homosteroid (29). i.e. a steroid analogue in which the C/D indane system is substituted by a decalin in which the rran -configuration is the thermodynamically favoured (Scheme 8.7). The conversion of the six-membered ring into one of five members is carried out at a later stage, under conditions that do not affect the preformed tran -junction. 

Within a programme aimed at the development of thyroid hormone analogues as potentially useful plasma cholesterol-lowering agents, the pyrida-zinone derivative SK F L-94901 (98) has been prepared and investigated in the U.K. [419-422]. Whereas naturally occurring thyroid hormones cannot be employed for this purpose because of their undesirable effect on heart rate, (98) has been found to represent a potent thyromimetic which retains hepatic activity but lacks cardiac activity. Structural modifications and QSAR studies have been carried out [422]. 

Mass-spectral fragmentation of cholesterol and its analogues with A -unsaturation pathways to account for (M —85) and (M 111) ions... 

The answer is d. (Hardman, pp 885-886. Katzung, pp 591-592.) Atorvastatin is a structural analogue of an intermediate formed from the action of HMG-CoA reductase. This could result in a modest decrease in plasma cholesterol. Hepatic cholesterol synthesis may decrease significantly however, nonhepatic tissues increase their rate of synthesis as a compensatory mechanism. The other and perhaps more important effect of the HMG-CoA inhibitors is to increase high-affinity LDL receptors. The plasma LDL is lowered by this action because of an increase in the catabolic rate of LDL and hepatic extraction of LDL precursors. 

On the basis of these experiments, we anticipated that conformationally constrained analogues of our open chain diamides (1 and 2) may increase activity against cancer cell lines. In (3-lactam chemistry, this kind of hypothesis had been tested, and it was established that certain (3-lactams are more effective at lowering cholesterol in human plasma when compared to open-chain substrates [12-15]. Therefore, preparation of (3-lactams of type 3 and related compounds was necessary to investigate a comparative study with diamides 1 and 2. 

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