| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
| First Page | Previous Page | Next Page | Last Page |
| Synthesis of 9-oxononanoyl cholesterol by ozonization Boechzelt, H., B. Karten, et al. (1998), J Lipid Res 39(7): 1503-7. Abstract: A new route for the preparation of 9-oxononanoyl cholesterol (5) and its stable dimethylacetal (4) is described. The core aldehyde 5 is one of the major products formed during lipid peroxidation. The synthesis starts with the ozonization of oleic acid in methanol and further reduction with dimethyl sulfide to yield 9,9-dimethoxy nonanoic acid (2a). The condensation of 2a with cholesterol is achieved with N,N'-dicyclohexylcarbodiimide in dichloromethane to give 4. Further hydrolysis of 4 with the help of an acidic ion exchange resin yields 9-oxononanoyl cholesterol. |
| Synthesis of a biotin-tagged photoaffinity probe of 2-azetidinone cholesterol absorption inhibitors Frick, W., A. Bauer-Schafer, et al. (2003), Bioorg Med Chem 11(8): 1639-42. Abstract: The design and synthesis of a biotin-tagged photoreactive analogue C-4 of the cholesterol absorption inhibitor Ezetimibe is described. Photoaffinity labeling of intestinal brush border membrane vesicles with C-4 and subsequent streptavidin-biotin chromatography leads to selective extraction of a 145 kDa integral membrane protein as the molecular target for cholesterol absorption inhibitors. |
| Synthesis of a new neoglycolipid (AgH-1) and its effect upon the properties of dipalmitoylphosphatidylcholine: cholesterol liposomes Lissi, E. A., E. B. Abuin, et al. (1998), Arch Biochem Biophys 350(2): 137-44. Abstract: A new neoglycolipid (AgH-1) bearing carbohydrate units that mimics the antigenic determinant of the O-blood group was synthesized and the effect of its incorporation in dipalmitoylphosphatidylcholine (DPPC): cholesterol liposomes was evaluated. The results obtained show that AgH-1 is readily incorporated into DPPC:cholesterol liposomes. The conditions leading to the optimal incorporation are the result of a compromise between incorporation efficiency and incorporation extent. The presence of AgH-1 produces liposomes of smaller size, with only small changes in the properties of the bilayer. However, the data obtained employing diphenylhexatriene and laurodan as fluorescence probes and merocyanine 540 as optical probe suggest that AgH-1 incorporation leads to a small rigidization of the liposomes at temperatures lower than ca. 42 degrees C. |
| Synthesis of a novel series of cationic lipids that can act as efficient gene delivery vehicles through systematic heterocyclic substitution of cholesterol derivatives Gao, H. and K. M. Hui (2001), Gene Ther 8(11): 855-63. Abstract: The synthesis of a series of novel cationic lipids through the systematic substitution of cholesterol derivatives that could greatly enhance the delivery and expression of plasmid DNA in vitro and in vivo is described. Two of the newly synthesized lipids, designated as NCC4 and NCC10, were chosen to be studied in detail and gave much higher levels of gene expression than that which could be obtained with some of the conventional cationic polymers and cationic liposomes. In vivo studies with both NCC4 and NCC10 also showed better ability in delivering the reporter gene to the target cells through intrasplenic injection. In addition, by varying the DNA/lipid charge ratios, NCC4 and NCC10 can withstand serum inactivation in vitro. However, this does not correlate with the corresponding increase in the level of gene expression following systemic gene delivery with NCC4 and NCC10 in vivo. |
| Synthesis of C3 heteroatom-substituted azetidinones that display potent cholesterol absorption inhibitory activity McKittrick, B. A., K. Ma, et al. (1998), J Med Chem 41(5): 752-9. Abstract: The C3 phenylpropyl side chain of N-phenylazetidinones related to SCH 56524 was modified by replacing the hydroxymethylene with various isoelectronic or isosteric groups. Modifications at the 3' position led to less-active compounds; however, modifications at the 1' position provided compounds with improved cholesterol absorption inhibitory activity. An enantioselective route for the synthesis of C3 1'-sulfur-substituted azetidinones and the development of structure-activity relationships for this series of compounds are presented. |
| Synthesis of chimeric 7alpha-substituted estradiol derivatives linked to cholesterol and cholesterylamine Hussey, S. L., E. He, et al. (2002), Org Lett 4(3): 415-8. Abstract: We report the synthesis of 7alpha-substituted beta-estradiol derivatives bearing side chains terminated with cholesterol and 3beta-cholesterylamine. These chimeric compounds were designed to exhibit high affinity for estrogen receptors (ERs) and cellular plasma membranes to potentially enable regulated uptake of ERs by mammalian cells. Evaluation with recombinant yeast reporting compound-mediated ER dimerization revealed potencies similar to the antiestrogen ICI 182780. Compounds that efficiently deliver dominant negative ERs into cells may provide novel therapeutics against breast cancers. |
| Synthesis of cholesterol modified cationic lipids for liposomal drug delivery of antisense oligonucleotides Zimmer, A., S. A. Aziz, et al. (1999), Eur J Pharm Biopharm 47(2): 175-8. Abstract: The paper describes a novel synthesis of cholest-5-en-3 beta-yl-6-aminohexyl ether (AH-Chol). AH-Chol was used to prepare positively charged liposomes. The liposomes consisted of phospholipon 90H and the cationic cholesterol derivative in an equimolar ratio. Liposome preparation was achieved by membrane homogenization after rehydration of a dry lipid film. Oligonucleotides (ODN) were adsorbed to the cationic liposomes very efficiently. At an ODN/liposome ratio of 1:5 (10:50 micrograms/ml) 84.2 +/- 5.4% of the ODNs were bound to the liposomal membrane. Within the range of 1:40 and 1:100 charge neutralization occurred and the liposome dispersion showed an increase in particle size due to aggregation. Below or above this range of charge neutralization the ODN loaded liposome preparation was physically stable, no sedimentation, increase of vesicle size or vesicle aggregation occurred. |
| Synthesis of cholesterol-carborane conjugate for targeted drug delivery Ji, B., G. Peacock, et al. (2002), Bioorg Med Chem Lett 12(17): 2455-8. Abstract: The cholesterol-carborane conjugate has been designed and synthesized to selectively deliver boron to tumor cells by means of reconstituted low-density lipoprotein. The chemical stability and cytotoxicity of the new compound have been examined. Several methods have been evaluated for incorporation of the compound into LDL. |
| Synthesis of cholesterol-containing cationic amphiphiles with heterocyclic bases Konstantinova, T. V., V. N. Klykov, et al. (2001), Bioorg Khim 27(6): 453-6. Abstract: A number of cationic derivatives of cholesterol containing polar residues of N-methylimidazole, pyridine, N-methylmorpholine, and 4-N,N-dimethyaminopyridine were synthesized by the interaction of the corresponding heterocyclic bases with cholesterol 5-bromopentanoate followed by the treatment with methyl iodide in the case of tertiary amines. In addition, N-(4-cholesteryloxycarbonylbutyl)piperazine was obtained for the preparation of pH-sensitive liposomes. |
| Synthesis of fluorescent biochemical tools related to the 2-azetidinone class of cholesterol absorption inhibitors Burnett, D. A., M. A. Caplen, et al. (2002), Bioorg Med Chem Lett 12(3): 315-8. Abstract: Fluorescent analogues of the cholesterol absorption inhibitor (CAI), Sch 58235, have been designed and synthesized as single enantiomers. Biological testing reveals that they are potent CAIs and are suitable tools for the investigation of the azetidinone CAI mechanism of action (MOA). |
| Synthesis of iodinated biochemical tools related to the 2-azetidinone class of cholesterol absorption inhibitors Burnett, D. A., M. A. Caplen, et al. (2002), Bioorg Med Chem Lett 12(3): 311-4. Abstract: The discoveries of Sch 48461 and Sch 58235 and their novel pharmacology of inhibition of cholesterol absorption have prompted efforts to determine their biological mechanism of action (MOA). To this end, a series of radioiodinated analogues with good to excellent in vivo activity have been designed and synthesized as single enantiomers. They are structurally consistent with the allowable SAR of the 2-azetidinone class of cholesterol absorption inhibitors. |
| Synthesis of lipid and cholesterol hydroperoxide standards Armstrong, D. and R. W. Browne (1998), Methods Mol Biol 108: 139-45. |
| Synthesis of novel 4,1-benzoxazepine derivatives as squalene synthase inhibitors and their inhibition of cholesterol synthesis Miki, T., M. Kori, et al. (2002), J Med Chem 45(20): 4571-80. Abstract: Modification of the carboxyl group at the 3-position and introduction of protective groups to the hydroxy group of the 4,1-benzoxazepine derivative 2 (metabolite of 1) were carried out, and the inhibitory activity for squalene synthase and cholesterol synthesis in the liver was investigated. Among these compounds, the glycine derivative 3a and beta-alanine derivative 3f exhibited the most potent inhibition of squalene synthase prepared from HepG2 cells (IC(50) = 15 nM). On the other hand, the piperidine-4-acetic acid derivative 4a, which was prepared by acetylation of 3j, was the most effective inhibitor of cholesterol synthesis in rat liver (ED(50) = 2.9 mg/kg, po). After oral administration, 4a was absorbed and rapidly hydrolyzed to deacylated 3j. Compound 3j was detected mainly in the liver, but the plasma level of 3j was found to be low. Compounds 3j and 4a were found to be competitive inhibitors with respect to farnesyl pyrophosphate. Further evaluation of 4a as a cholesterol-lowering and antiatherosclerotic agent is underway. |
| Synthesis of prostaglandins and thromboxane B2 by cholesterol-fed rabbits Wang, T., P. Falardeau, et al. (1991), Arterioscler Thromb 11(3): 501-8. Abstract: Alterations in the synthesis of thromboxane A2 (TxA2) and prostacyclin have been implicated in the development of atherosclerosis. We measured the amounts of the degradation products of these substances, TxB2 and 6-oxo-prostaglandin F1 alpha (6-oxo-PGF1 alpha), respectively, as well as PGE2, that were synthesized by slices and the luminal surfaces of aortas from rabbits fed either a control diet or a diet supplemented with cholesterol and peanut oil. For these studies, we developed conditions that were designed to minimize the autoinactivation of cyclooxygenase during removal and preparation of the tissue. Pretreatment of aortas with a medium containing ibuprofen and EDTA resulted in an approximately twofold increase in 6-oxo-PGF1 alpha production upon subsequent incubation. Despite the increased lipid peroxidation associated with atherosclerotic lesions, we observed no changes in either aortic 6-oxo-PGF1 alpha production or in the levels of its major urinary metabolite, 2,3-dinor-6-oxo-PGF1 alpha, after as long as 15 weeks of dietary supplementation with cholesterol and peanut oil. Similarly, synthesis of PGE2 by aortic slices and the aortic lumen was the same in cholesterol-fed and control rabbits. In contrast to aortic 6-oxo-PGF1 alpha and PGE2 synthesis, there was a dramatic 10-fold increase in TxB2 released from slices of thoracic aorta after 15 weeks on the atherogenic diet. This was much greater than the approximately twofold increase in the synthesis of TxB2 by the luminal surface of the thoracic aorta, suggesting that the primary site of TxB2 synthesis in the aorta is in the inner part of the blood vessel.(ABSTRACT TRUNCATED AT 250 WORDS) |
| Synthetic amphipathic helical peptides that mimic apolipoprotein A-I in clearing cellular cholesterol Mendez, A. J., G. M. Anantharamaiah, et al. (1994), J Clin Invest 94(4): 1698-705. Abstract: Clearance of excess cholesterol from cells by HDL is facilitated by the interaction of HDL apolipoproteins with cell-surface binding sites or receptors, a process that may be important in preventing atherosclerosis. In this study, synthetic peptides containing 18-mer amphipathic helices of the class found in HDL apolipoproteins (class A) were tested for their abilities to remove cholesterol and phospholipid from cultured sterol-laden fibroblasts and macrophages and to interact with cell-surface HDL binding sites. Lipid-free peptides containing two identical tandem repeats of class A amphipathic helices promoted cholesterol and phospholipid efflux from cells and depleted cellular cholesterol accessible for esterification by acyl CoA/cholesterol acyltransferase, similar to what was observed for purified apolipoprotein A-I. Peptide-mediated removal of plasma membrane cholesterol and depletion of acyl CoA/cholesterol acyltransferase-accessible cholesterol appeared to occur by separate mechanisms, as the latter process was less dependent on extracellular phospholipid. The dimeric amphipathic helical peptides also competed for high-affinity HDL binding sites on cholesterol-loaded fibroblasts and displayed saturable high-affinity binding to the cell surface. In contrast, peptides with a single helix had little or no ability to remove cellular cholesterol and phospholipid, or to interact with HDL binding sites, suggesting that cooperativity between two or more helical repeats is required for these activities. Thus, synthetic peptides comprising dimers of a structural motif common to exchangeable apolipoproteins can mimic apolipoprotein A-I in both binding to putative cell-surface receptors and clearing cholesterol from cells. |
| Systematic review of dietary intervention trials to lower blood total cholesterol in free-living subjects Tang, J. L., J. M. Armitage, et al. (1998), Bmj 316(7139): 1213-20. Abstract: OBJECTIVES: To estimate the efficacy of dietary advice to lower blood total cholesterol concentration in free-living subjects and to investigate the efficacy of different dietary recommendations. DESIGN: Systematic overview of 19 randomised controlled trials including 28 comparisons. SUBJECTS: Free-living subjects. INTERVENTIONS: Individualised dietary advice to modify fat intake. MAIN OUTCOME MEASURE: Percentage difference in blood total cholesterol concentration between the intervention and control groups. RESULTS: The percentage reduction in blood total cholesterol attributable to dietary advice after at least six months of intervention was 5.3% (95% confidence interval 4.7% to 5.9%). Including both short and long duration studies, the effect was 8.5% at 3 months and 5.5% at 12 months. Diets equivalent to the step 2 diet of the American Heart Association were of similar efficacy to diets that aimed to lower total fat intake or to raise the polyunsaturated to saturated fatty acid ratio. These diets were moderately more effective than the step 1 diet of the American Heart Association (6.1% v 3.0% reduction in blood total cholesterol concentration; P<0.0001). On the basis of reported food intake, the targets for dietary change were seldom achieved. The observed reductions in blood total cholesterol concentrations in the individual trials were consistent with those predicted from dietary intake on the basis of the Keys equation. CONCLUSIONS: Individualised dietary advice for reducing cholesterol concentration is modestly effective in free-living subjects. More intensive diets achieve a greater reduction in serum cholesterol concentration. Failure to comply fully with dietary recommendations is the likely explanation for this limited efficacy. |
| Systematic review on the risk and benefit of different cholesterol-lowering interventions Bucher, H. C., L. E. Griffith, et al. (1999), Arterioscler Thromb Vasc Biol 19(2): 187-95. Abstract: Meta-analyses have investigated the efficacy of cholesterol-lowering interventions in relation to the underlying risk of coronary heart disease and the extent and duration of cholesterol reduction. We systematically reviewed the efficacy of antilipidemic interventions on major mortality outcomes in relation to drug classes. We searched MEDLINE and EMBASE from 1966 through October 1996 for randomized, controlled trials of any cholesterol-lowering interventions reporting mortality data. We included 59 trials involving 85 431 participants in the intervention and 87 729 participants in the control groups. We pooled these trials into 7 pharmacological categories of cholesterol-lowering interventions: statins (13 trials), fibrates (12 trials), resins (8 trials), hormones (8 trials), niacin acid (2 trials), n-3 fatty acids (3 trials), and dietary interventions (16 trials). Of the cholesterol-lowering interventions, only statins showed a large and statistically significant reduction in mortality from coronary heart disease (risk ratio, 0.66; 95% confidence interval CI, 0.54 to 0. 79) and from all causes (risk ratio, 0.75; 95% CI, 0.65 to 0.86). For both all-cause and cardiovascular mortality, the difference between statins and the combined estimate of the other classes of agents was unlikely to be due to chance (P<0.02 for both comparisons). Meta-regression analysis demonstrated that variability in results across trials could be largely explained on the basis of differences in the magnitude of cholesterol reduction. Statins have the largest effect on the reduction of cardiovascular and all-cause mortality, and this result recommends their use in preference to other antilipidemic agents. The greater effect of statins is likely due to the larger reduction in cholesterol. |
| Systematic underestimation of association between serum cholesterol concentration and ischaemic heart disease in observational studies: data from the BUPA study Law, M. R., N. J. Wald, et al. (1994), Bmj 308(6925): 363-6. Abstract: OBJECTIVE--To estimate the size of the association between serum concentration of low density lipoprotein cholesterol and mortality from ischaemic heart disease. DESIGN--Prospective study of total serum cholesterol concentration and mortality from ischaemic heart disease in 21,515 men (538 deaths) and study of total cholesterol concentration measured on two occasions an average of three years apart in 5696 men in whom low density lipoprotein cholesterol concentration was also measured on the second occasion. SUBJECTS--Men who attended the medical centre of the British United Provident Association (BUPA) in London between 1975 and 1982. MAIN OUTCOME MEASURE--The difference in mortality from ischaemic heart disease for a 0.6 mmol/l difference in concentration of low density lipoprotein cholesterol after adjustment for, firstly, regression dilution bias, which arises from the random fluctuation of serum cholesterol concentration in people over time, and, secondly, the surrogate dilution effect, which arises because differences in total cholesterol concentration between people reflect smaller differences in low density lipoprotein cholesterol concentration. RESULTS--The observed difference in mortality from ischaemic heart disease associated with a difference of 0.6 mmol/l in total serum cholesterol concentration was 17% but increased to 24% after correction for the regression dilution bias and to 27% (95% confidence interval 21% to 33%) after adjustment for both sources of underestimation, which provides an estimate of the difference in mortality for a true difference of 0.6 mmol/l in low density lipoprotein cholesterol concentration. The association was greater at younger ages. The estimated decrease in mortality from all causes was 6% before and 10% (1% to 17%) after adjustment for the two sources of underestimation. There was no excess mortality from any cause associated with low cholesterol concentration. CONCLUSIONS--The association between serum cholesterol concentration and ischaemic heart disease is materially stronger than directly inferred from prospective studies. This has important implications for the health benefit of achieving low cholesterol concentrations. |
| Systeme International (SI) units to express the concentrations of triglycerides and cholesterol Masse, J. (1991), J Am Coll Nutr 10(6): 675. |
| Systemic cholesterol microembolization syndrome masquerading as giant cell arteritis Jacobson, D. M. (1991), Surv Ophthalmol 36(1): 23-7. Abstract: Two patients with clinical features consistent with giant cell arteritis were found to have systemic cholesterol microembolization syndromes. Diagnostic confirmation was established by a muscle biopsy in one patient and by a kidney biopsy in the other. Systemic cholesterol embolization can masquerade as a variety of disorders, including vasculitis, and should be considered in a patient with suspected giant cell arteritis who has a negative temporal artery biopsy. |