4，4-二甲基-3β，7β-二羟基石胆酸衍生物的设计、合成及其促HMGCR泛素化降解的活性研究
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摘要
3-羟基-3-甲基戊二酰辅酶A还原酶(HMGCR)是体内胆固醇生物合成的关键酶,HMGCR的泛素化降解是一种降低胆固醇水平的新途径。本论文在课题组前期工作的基础上,围绕高活性、高特异性促HMGCR泛素化降解的新化合物发现开展了以下研究工作：
一、4,4-二甲基-3β,7β-二羟基石胆酸衍生物的设计、合成及其促HMGCR泛素化降解的活性研究
1、以石胆酸为起始原料,在引入4,4-二甲基、3β,7β-二羟基的基础上,重点对D-环侧链进行结构改造,设计、合成了A、B、C、D四个化合物库共49个新化合物,利用谱学方法对所有化合物的结构进行了表征。
2、促HMGCR泛素化降解活性的研究结果表明,侧链官能团碳到D-环的链长分别为5、6、7个碳原子、侧链官能团为亲水性的伯、仲、叔羟基或羧基时,所有化合物均具有较好的促HMGCR泛素化降解活性,D-环侧链链长为5个碳原子为相对最佳长度,叔羟基为相对最佳官能团。进一步的活性研究结果显示,化合物2-121的活性接近25-HC,而化合物2-74的活性高于25-HC。
3、将化合物2-74、2-121与CHO-7细胞孵育,采用细胞生长实验的方法,初步推断该类目标分子能有效抑制细胞内源性胆固醇的合成。
4、初步研究了化合物2-74、2-121的作用机制。采用Real-time PCR实验检测LXR信号通路中的靶基因ABCG5、SREBP-1、FAS,结果显示化合物2-74、2-121基本上不激活LXR信号通路,提示4,4-二甲基-3β,7β-二羟基石胆酸衍生物在基本上不激活LXR信号通路方面不同于25-HC。化合物2-74及2-121有可能成为通过促HMGCR泛素化降解降低体内胆固醇水平的潜在先导化合物。
二、以化合物2-69为活性基团的小分子探针的设计与合成探索
1、为了探索石胆酸衍生物促HMGCR泛素化降解的可能靶标,在4,4-二甲基、3β,7β-二羟基石胆酸衍生物促HMGCR泛素化降解活性及构效关系研究的基础上,以具有较好促HMGCR泛素化降解活性和易于修饰的含羧基官能团的化合物2-69为活性基团、三氟甲基苯基二氮烯类为光亲和标记基团、多聚乙二醇链为连接链、生物素为报告基团,设计了PAL-ABPP探针分子PALCAD。
2、设计并尝试了多种合成途径。虽然由于所得到的粗产物量少,纯化困难,未能获得高纯度的目标探针分子PALCAD,但粗产物的核磁共振氢谱和质谱均显示了该分子的特征信号。
小分子探针PALCAD的重复合成和纯化工作正在进行中。在已知构效关系的基础上,该类石胆酸衍生物D-环侧链官能团类型的拓展(如NH2、NHR、NHCO等)及氢键给(受)体的影响也将后续进行。
3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is the key enzyme of cholesterol biosynthesis in vivo, the ubiquitination and degradation of HMGCR is a new way to reduce cholesterol levels. On the basis of the research group's preliminary work, this dissertation was focused on finding novel compounds with high activity and specificity which can promote the ubiquitination and degradation of HMGCR, the research work was carried out as follows:
Part I. Design and synthesis of4,4-dimethyl-3β,7β-dihydroxylithocholic acid derivatives and studies on their ubiquitination and degradation of HMGCR
1. With lithocholic acid as the starting material and then forming a4,4-dimethyl-3β,7β-dihydroxy substituted unit, four compound libraries A, B, C, D, including totally49new compounds were designed and synthesized by modifying the D-ring of the side chain. All compounds'structures were characterized by spectroscopic methods.
2.The results of promoting the ubiquitination and degradation of HMGCR showed that when the chain length has5,6,7carbon atoms and the side-chain functional group is hydrophilic, such as primary, secondary, tertiary hydroxyl group or carboxyl group, all the compounds have a better activity in promoting the ubiquitination and degradation of HMGCR. The D-ring side chain with five carbon atoms is relatively optimum length and the tertiary hydroxyl group is maybe the best functional group. Further tested showed that the activity of compound2-121is close to25-HC while compound2-74is stronger than25-HC.
3. Incubation compounds2-74and2-121with CHO-7cells, it was preliminary confirmed that this type of target molecules can effectivity inhibit the endogenous synthesis of cholesterol in the cell by using cell growth experiments method.
4. The preliminary mechanism of compounds2-74and2-121on ubiquitination and degradation of HMGCR was also studied. It was shown that compounds2-74and2-121almost do not activate LXR signaling pathway by using the Real-time PCR test to assay target genes ABCG5, SREBP-1, FAS, which indicated that4,4-dimethyl-3β,7β-dihydroxylithocholic acid derivatives do not activate LXR signaling pathway without25-HC. Compounds2-74and2-121may be potential lead compounds by promoting the ubiquitination and degradation of HMGCR to reduce cholesterol levels in vivo.
Part Ⅱ. Design and Synthesis of small molecular probe based on compound2-69
1. In order to explore the potential targets of lithocholic acid derivatives on promoting the ubiquitination and degradation of HMGCR. The probe PALCAD was designed on the basis of SAR of lithocholic acid derivatives and with compound2-69as the active group, trifluoromethylphenyl diazirine as the photoaffinity labeling group, poly ethylene glycol chain as the connecting chain, and biotin as the reporting group.
2. Several synthetic methods were tried and carried out, NMR and mass spectrometry of the crude product showed the characteristic signals of PALCAD although we failed in obtaining the high purity probe PALCAD.
The synthesis and purification of the small molecular probe PALCAD is still ongoing. The expansion of functional group (NH2, NHR, NHCO, etc.) for D-ring side chain and the study of effectiveness of the hydrogen bond donating (accepting) will be continued on the basis of the previous SAR study.
一、4,4-二甲基-3β,7β-二羟基石胆酸衍生物的设计、合成及其促HMGCR泛素化降解的活性研究
1、以石胆酸为起始原料,在引入4,4-二甲基、3β,7β-二羟基的基础上,重点对D-环侧链进行结构改造,设计、合成了A、B、C、D四个化合物库共49个新化合物,利用谱学方法对所有化合物的结构进行了表征。
2、促HMGCR泛素化降解活性的研究结果表明,侧链官能团碳到D-环的链长分别为5、6、7个碳原子、侧链官能团为亲水性的伯、仲、叔羟基或羧基时,所有化合物均具有较好的促HMGCR泛素化降解活性,D-环侧链链长为5个碳原子为相对最佳长度,叔羟基为相对最佳官能团。进一步的活性研究结果显示,化合物2-121的活性接近25-HC,而化合物2-74的活性高于25-HC。
3、将化合物2-74、2-121与CHO-7细胞孵育,采用细胞生长实验的方法,初步推断该类目标分子能有效抑制细胞内源性胆固醇的合成。
4、初步研究了化合物2-74、2-121的作用机制。采用Real-time PCR实验检测LXR信号通路中的靶基因ABCG5、SREBP-1、FAS,结果显示化合物2-74、2-121基本上不激活LXR信号通路,提示4,4-二甲基-3β,7β-二羟基石胆酸衍生物在基本上不激活LXR信号通路方面不同于25-HC。化合物2-74及2-121有可能成为通过促HMGCR泛素化降解降低体内胆固醇水平的潜在先导化合物。
二、以化合物2-69为活性基团的小分子探针的设计与合成探索
1、为了探索石胆酸衍生物促HMGCR泛素化降解的可能靶标,在4,4-二甲基、3β,7β-二羟基石胆酸衍生物促HMGCR泛素化降解活性及构效关系研究的基础上,以具有较好促HMGCR泛素化降解活性和易于修饰的含羧基官能团的化合物2-69为活性基团、三氟甲基苯基二氮烯类为光亲和标记基团、多聚乙二醇链为连接链、生物素为报告基团,设计了PAL-ABPP探针分子PALCAD。
2、设计并尝试了多种合成途径。虽然由于所得到的粗产物量少,纯化困难,未能获得高纯度的目标探针分子PALCAD,但粗产物的核磁共振氢谱和质谱均显示了该分子的特征信号。
小分子探针PALCAD的重复合成和纯化工作正在进行中。在已知构效关系的基础上,该类石胆酸衍生物D-环侧链官能团类型的拓展(如NH2、NHR、NHCO等)及氢键给(受)体的影响也将后续进行。
3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is the key enzyme of cholesterol biosynthesis in vivo, the ubiquitination and degradation of HMGCR is a new way to reduce cholesterol levels. On the basis of the research group's preliminary work, this dissertation was focused on finding novel compounds with high activity and specificity which can promote the ubiquitination and degradation of HMGCR, the research work was carried out as follows:
Part I. Design and synthesis of4,4-dimethyl-3β,7β-dihydroxylithocholic acid derivatives and studies on their ubiquitination and degradation of HMGCR
1. With lithocholic acid as the starting material and then forming a4,4-dimethyl-3β,7β-dihydroxy substituted unit, four compound libraries A, B, C, D, including totally49new compounds were designed and synthesized by modifying the D-ring of the side chain. All compounds'structures were characterized by spectroscopic methods.
2.The results of promoting the ubiquitination and degradation of HMGCR showed that when the chain length has5,6,7carbon atoms and the side-chain functional group is hydrophilic, such as primary, secondary, tertiary hydroxyl group or carboxyl group, all the compounds have a better activity in promoting the ubiquitination and degradation of HMGCR. The D-ring side chain with five carbon atoms is relatively optimum length and the tertiary hydroxyl group is maybe the best functional group. Further tested showed that the activity of compound2-121is close to25-HC while compound2-74is stronger than25-HC.
3. Incubation compounds2-74and2-121with CHO-7cells, it was preliminary confirmed that this type of target molecules can effectivity inhibit the endogenous synthesis of cholesterol in the cell by using cell growth experiments method.
4. The preliminary mechanism of compounds2-74and2-121on ubiquitination and degradation of HMGCR was also studied. It was shown that compounds2-74and2-121almost do not activate LXR signaling pathway by using the Real-time PCR test to assay target genes ABCG5, SREBP-1, FAS, which indicated that4,4-dimethyl-3β,7β-dihydroxylithocholic acid derivatives do not activate LXR signaling pathway without25-HC. Compounds2-74and2-121may be potential lead compounds by promoting the ubiquitination and degradation of HMGCR to reduce cholesterol levels in vivo.
Part Ⅱ. Design and Synthesis of small molecular probe based on compound2-69
1. In order to explore the potential targets of lithocholic acid derivatives on promoting the ubiquitination and degradation of HMGCR. The probe PALCAD was designed on the basis of SAR of lithocholic acid derivatives and with compound2-69as the active group, trifluoromethylphenyl diazirine as the photoaffinity labeling group, poly ethylene glycol chain as the connecting chain, and biotin as the reporting group.
2. Several synthetic methods were tried and carried out, NMR and mass spectrometry of the crude product showed the characteristic signals of PALCAD although we failed in obtaining the high purity probe PALCAD.
The synthesis and purification of the small molecular probe PALCAD is still ongoing. The expansion of functional group (NH2, NHR, NHCO, etc.) for D-ring side chain and the study of effectiveness of the hydrogen bond donating (accepting) will be continued on the basis of the previous SAR study.
引文
[1]Small, D. M.; Shipley, G. G. Physical-chemical basis of lipid deposition in atherosclerosis. Science,1974,185 (4147),222-229.
[2]Casserly, I. P.; Topol, E. J.. Convergence of atherosclerosis and alzheimer's disease:Cholesterol, inflammation, and misfolded proteins. Discov. Med.,2004, 4(22),149-156.
[3]Lewington, S.; Whitlock, G..;, Clarke, R.; Sherliker, P.; Emberson, J.; Halsey, J.; Qizilbash, N.; Peto, R.; Collins, R.. Blood cholesterol and vascular mortality by age, sex, and blood pressure:a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet,2007,370 (9602), 1829-1839.
[4]Murray, C. J.; Lauer, J. A.; Hutubessy, R. C.; Niessen, L.; Tomijima, N.; Rodgers, A.; Lawes, C. M.; Evans, D. B.. Effectiveness and costs of interventions to lower systolic blood pressure and cholesterol:a global and regional analysis on reduction of cardiovascular-disease risk. Lancet,2003,361 (9359),717-725.
[5]Keys, A.. Coronary heart disease-the global picture. Atherosclerosis,1975,22 (2),149-192.
[6]Fonseca, A. C.; Resende, R.; Oliveira, C. R.; Pereira, C. M.. Cholesterol and statins in Alzheimer's disease:current controversies. Exp. Neurol,2010,223 (2), 282-293.
[7]Wolozin, B.. Cholesterol and the biology of Alzheimer's disease. Neuron,2004, 41(1),7-10.
[8]Wang, H. H.; Portincasa, P.; Mendez-Sanchez, N.; Uribe, M.; Wang, D. Q.. Effect of ezetimibe on the prevention and dissolution of cholesterol gallstones. Gastmenterology,2008,134 (7),2101-2110.
[9]王卫珍.他汀类降脂药的药理作用和应用指导.中华临床医学研究杂志2007,13(15),2243-2244.
[10]骆雷鸣,刘果树.他汀类药物的临床药理和应用.药物不良反应(ADRJ)2001,(3),145-150.
[11]Goldstein, J. L.; Brown, M. S.. Regulation of the mevalonate pathway. Nature, 1990,343 (6257),425-430.
[12]Gil, G.; Faust, J. R.; Chin, D. J.; Goldstein, J. L.; Brown, M. S.. Membrane-bound domain of HMG CoA reductase is required for sterol-enhanced degradation of the enzyme. Cell,1985,41 (1),249-258.
[13]Roitelman, J.; Olender, E. H.; Bar-Nun, S.; Dunn, WA. Jr.; Simoni, R. D.. Immunological evidence for eight spans in the membrane domain of 3-hydroxy-3-methylglutaryl coenzyme A reductase:implications for enzyme degradation in the endoplasmic reticulum. J. Cell Biol,1992,117 (5),959-973.
[14]左玉,冯丽霞,魏世芳。胆固醇的研究及应用。太原师范学院学报(自然科学版),2010，9(4)，104-107.
[15]Brown, M. S.; Goldstein, J. L.. The SREBP pathway:regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell, 1997,89 (3),331-340.
[16]郭晓强,郭振清SREBP介导的胆固醇生物合成反馈调节.(?)Chemistry Of Life, 2007,27 (4),292-294.
[17]Kim, J. B.; Spiegelman, B. M.. ADD1/SREBP1 promotes adipocyte differentiation and gene expression linked to fatty acid metabolism. Genes. Dev.,1996,10 (9),1096-1107.
[18]Osborne, T. F.. Transcriptional control mechanisms in the regulation of cholesterol balance. Crit. Rev. Eukaryot. Gene Expr.,1995,5 (3-4),317-335.
[19]Ericsson, J.; Jackson, S. M.; Edwards, P. A.. Synergistic binding of sterol regulatory element-binding protein and NF-Y to the farnesyl diphosphate synthase promoter is critical for sterol-regulated expression of the gene. J. Biol. Chem.1996,271 (40),24359-24364.
[20]Magana, M. M.; Osborne, T. F.. Two tandem binding sites for sterol regulatory element binding proteins are required for sterol regulation of fatty-acid synthase promoter. J Biol Chem,1996,271 (51),32689-32694.
[21]Oliner, J. D.; Andresen, J. M.; Hansen, S. K.; Zhou, S.; Tjian, R.. SREBP transcriptional activity is mediated through an interaction with the CREB-binding protein. Genes Dev,1996,10 (22),2903-2911.
[22]Rawson, R. B.. Control of lipid metabolism by regulated intramembrane proteolysis of sterol regulatory element binding proteins (SREBPs). Biochem. Soc. Symp.,2003, (70),221-231.
[23]Takahata, R.; Matsumtlra, H.; Kantha, S. S.; Kubo, E.; Kawase, K.; Sakai, T.; Hayaishi, O.. Intravenous administration of inorganic selenium compounds, inhibitors of prostaglandin D synthase, inhibits sleep in freely moving rats. Brain Res,1993,623 (1),65-71.
[24]Steck, T. L.; Lange, Y.. SCAP, an ER sensor that regulates cell cholesterol. Dev Cell,2002,3 (3),306-308.
[25]Adams, C. M.; Reitz, J.; De Brabander, J. K.; Feramisco, J. D.; Li, L.; Brown, M. S.; Goldstein, J. L.. Cholesterol and 25-hydroxycholesterol inhibit activation of SREBPs by different mechanisms, both involving SCAP and insigs. J. Biol. Chem.,2004,279 (50),52772-52780.
[26]Brown, A. J.; Sun, L.; Feramisco, J. D.; Brown, M. S.; Goldstein, J. L. Cholesterol addition to ER membranes alters conformation of SCAP, the SREBP escort protein that regulates cholesterol metabolism. Mol. Cell.,2002, 10(2),237-245.
[27]Adams, C. M.; Goldstein, J. L.; Brown, M. S.. Cholesterol-induced conformational change in SCAP enhanced by Insig proteins and mimicked by cationic amphiphiles. Proc. Natl. Acad. Sci. USA,2003,100 (19), 10647-10652.
[28]Bucher, N. L.; Overath, P.; Lynen, F.. β-Hydroxy-(3-methylglutaryl coenzyme A reductase, cleavage and condensing enzymes in relation to cholesterol formation in rat liver. Biochim Biophys Acta,1960,40,491-501.
[29]Siperstein, M. D.; Fagan, V. M.. Feedback control of mevalonate synthesis by dietary cholesterol. J Biol Chem,1966,241 (3),602-609.
[30]Sever, N.; Song, B. L.; Yabe, D.; Goldstein, J. L.; Brown, M. S.; DeBose-Boyd, R.A.Jnsig-dependent ubiquitination and degradation of mammalian 3-hydroxy-3-methylglutaryl-Co A reductase stimulated by sterols and geranylgeraniol. J. Biol. Chem.,2003,278 (52),52479-52490.
[31]Sever, N.; Yang, T.; Brown, M. S.; Goldstein, J. L.; DeBose-Boyd, R. A.. Accelerated degradation of HMGCoA reductase mediated by binding of insig-1 to its sterol-sensing domain. Mol. Cell,2003,11 (1),25-33.
[32]Brown, M. S.; Goldstein, J. L.. A receptor-mediated path way for cholesterol homeostasis. Science,1986,232 (4746),34-41.
[33]Kajinami, K.; Takekoshi, N.. Cholesterol absorption inhibitors in development as potential therapeutics. Expert. Opin. Investig. Drugs.,2002,11 (6),831-835.
[34]Miettinen, T. A.. Cholesterol absorption inhibition:a strategy for cholesterol-lowering therapy. Int. J. Clin. Pract,2001,55 (10),710-716.
[35]Ge, L.; Qi, W.; Wang, L. J.; Miao, H. H.; Qu, Y. X.; Li, B. L.; Song, B. L. Flotillins play an essential role in Niemann-Pick Cl-like 1-mediated cholesterol uptake. Proc. Nat.l Acad. Sci. USA.,2011,108 (2),551-556.
[36]Knopp, R. H.; Gitter, H.; Truitt, T.; Bays, H.; Manion, C. V.; Lipka, L. J.; LeBeaut, A. P.; Suresh, R.; Yang, B.; Veltri, E. P.. Effects of ezetimibe, a new cholesterol absorption inhibitor,on plasma lipids in patients with primary hypercholesterolemia. Eur. Heart J.,2003,24 (8),729-741.
[37]Mitka, M.. Cholesterol drug controversy continues. JAMA,2008,299 (19), 2266.
[38]Taylor, A. J.; Villines, T. C.; Stanek, E. J.; Devine, P.; Griffen, L.; Miller, M.; Weissman, N. J.; Turco, M.. Extended-release niacin or ezetimibe and carotid intima-media thickness. N. Engl. J. Med.,2009,361 (22),2113-2122.
[39]付春.降血脂手性新药伊泽替米得合成,2007, (5),29-31.
[40]Ballantyne, C. M.; Olsson, A.G.; Cook, T. J.; Mercuri, M. F.; Pedersen, T. R.; Kjekshus, J.. Influence of low high-density Lipoprotein cholesterol and elevated triglyceride on coronary heart disease events and response to simvastatin therapy in 4S. Circulaion,2001,104 (25),3046-3051.
[41]Kastelein, J. J.; Akdim, F.; Stroes, E. S.; Zwinderman, A. H.; Bots, M. L.; Stalenhoef, A. F.; Visseren, F. L.; Sijbrands, E. J.; Trip, M. D.; Stein, E. A.; Gaudet, D.; Duivenvoorden, R.; Veltri, E. P.; Marais, A. D.; de Groot, E.. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N. Engl. J. Med.,2008,358 (14),1431-1443.
[42]Negredo, E.; Molto, J.; Puig, J.; Cinquegrana, D.; Bonjoch, A.; Perez-Alvarez, N.; Lopez-Blazquez, R.; Blanco, A.; Clotet, B.; Rey-Joly, C. Ezetimibe, a promising lipid-lowering agent for the treatment of dyslipidaemia in HIV infected patients with poor response to statins. AIDS.,2006,20 (17), 2159-2164.
[43]Giandomenico, V.; Simonsson, M.; Gronroos, E.; Ericsson, J.. Coactivator-dependent acetylation stabilizes members of the SREBP family of transcription factors. Mol. Cell. Biol,2003,23 (7),2587-2599.
[44]Anderson, R. G.. Joe Goldstein and Mike Brown:from cholesterol homeostasis to new paradigms in membrane biology. Trends. Cell. Biol,2003,13 (10), 534-539.
[45]Maron, D. J.; Fazio, S.; Linton, M.F.. Current perspectives on stains. Circulation,2000,101 (2),207-213.
[46]陈明卫,杨明功。他汀类药物肌毒性及其他毒副反应的发现与警惕.实用糖尿病杂志，2005,1(4)，13-15.
[47]Law, M. R.; Wald, N. J.; Rudnicka, A. R.. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke:systematic review and meta-analysis. BMJ,2003,326 (7404),1423.
[48]Thompson, P. D.; Clarkson, P.; Karas, R. H.. Statin-associated myopathy. JAMA.,2003,289 (13),1681-1690.
[49]Roberts, W. C. The underused miracle drugs:the statin drugs are to atherosclerosis what penicillin was to infectious disease. Am. J. Cardiol,1996,78 (3),377-378
[50]Topol, E. J.. Intensive statin therapy--a sea change in cardiovascular prevention. N.Engl.J.Med.,2004,350 (15),1562-1564.
[51]Kiortsis, D. N.; Filippatos, T. D.; Mikhailidis, D. P.; Elisaf, M. S.; Liberopoulos, E. N.. Statin-associated adverse effects beyond muscle and liver toxicity. Atherosclerosis,2007,195 (1),7-16.
[52]Vasudevan, A. R.; Hamirani, Y. S.; Jones, P. H., Safety of statins:effects on muscle and the liver. Cleve. Clin. J. Med.,2005,72(11),990-993,996-1001.
[53]Farmer, J. A.. Learning from the cerivastatin experience. Lancet,2001,358 (9291),1383-1385.
[54]Editorial. The statin wars:why AstraZeneca must retreat. Lancet,2003,362 (9393),1341.
[55]DeBose-Boyd, R. A.2009,25,206.1.
[56]Song, B. L.; DeBose-Boyd, R. A.. Ubiquitination of 3-hydroxy-3-methylglutaryl-CoA reductase in permeabilized cells mediated by cytosolic E1 and a putative membrane-bound ubiquitin ligase. J. Biol. Chem., 2004,279 (27),28798-28806.
[57]Song, B. L.; Javitt, N. B.; DeBose-Boyd, R. A.. Insig-mediated degradation of HMG CoA reductase stimulatedby lanosterol, an intermediate in the synthesis of cholesterol. Cell. Metab.,2005,1 (3),179-189.
[58]Horton, J. D.; Shimomura, I.. Sterol regulatory element-binding proteins: activators of cholesterol and fatty acid biosynthesis. Curr. Opin. Lipidol.,1999, 10,143-150.
[59]Repa, J. J.; Mangelsdorf, D. J.. The role of orphan nuclear receptors in the regulation of cholesterol homeostasis. Annu. Rev. Cell. Dev. Biol,2000,16, 459-481.
[60]Venkateswaran, A.; Laffitte, B. A.; Joseph, S. B.; Mak, P. A.; Wilpitz, D. C.; Edwards, P. A.; Tontonoz, P.. Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXR. Proc. Natl. Acad. Sci. USA.,2000,97 (22), 12097-12102.
[61]Repa, J. J.; Mangelsdorf, D. J.. The liver X receptor gene team:potential new players in atherosclerosis. Nat. Med.,2002,8 (11),1243-1248.
[62]Peet, D. J.; Turley, S. D.; Ma, W.; Janowski, B. A.; Lobaccaro, J. M.; Hammer, R. E.; Mangelsdorf, D. J.. Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxy sterol receptor LXR alpha. Cell,1998,93 (5), 693-704.
[63]Repa, J. J.; Liang, G.; Ou, J.; Bashmakov, Y.; Lobaccaro, J. M.; Shimomura, I.; Shan, B.; Brown M, S.; Goldstein, J. L.; Mangelsdorf, D. J.. Regulation of mouse sterol regulatory element-binding protein-lc gene (SREBP-1c) by oxysterol receptors, LXRal-pha and LXRbeta. Genes. Dev.,2000,14 (22), 2819-2830.
[64]Joseph, S. B.; McKilligin, E.; Pei, L.; Watson, M. A.; Collins, A. R.; Laffitte, B. A.; Chen, M.; Noh, G.; Goodman, J.; Hagger, G. N.; Tran, J.; Tippin, T. K.; Wang, X.; Lusis, A. J.; Hsueh, W. A.; Law, R. E.; Collins, J. L.; Willson, T. M.; Tontonoz, P.. Synthetic LXR ligand inhibits the development of atherosclerosis in mice. Proc. Natl. Acad. Sci. USA.,2002,99 (11),7604-7609.
[65]Tang, J. J.; Li, J. G.; Qi, W.; Qiu, W. W.; Li, P. S.; Li, B. L.; Song, B. L. Inhibition of SREBP by a Small Molecule, Betulin,Improves Hyperlipidemia and Insulin Resistanceand Reduces Atherosclerotic Plaques. Cell. Metab., 2011,13 (1),44-56.
[66]Dang, Z.; Lin, A.; Ho, P.; Soroka, D.; Lee, K. H.; Huang, L.; Chen, C. H.. Synthesis and proteasome inhibition of lithocholic acid derivatives. Bioorg. Med. Chem. lett.,2011,21(7),1926-1928.
[67]Mizushina, Y.; Kasai, N.; Miura, K.; Hanashima, S.; Takemura, M.; Yoshida, H.; Sugawara, F.; Sakaguchi, K.. Structural relationship of lithocholic acid derivatives binding to the N-terminal 8-kDa domain of DNA polymerase beta. Biochemistry.,2004,43(33),10669-10677.
[68]Goldberg, A. A.; Beach, A.; Davies, G. F.; Harkness, T. A.; Leblanc, A.; Titorenko, V. I.. Lithocholic bile acid selectively kills neuroblastoma cells, while sparing normal neuronal cells. Oncotarget.,2011,2(10),761-782.
[69]Tochtrop, G. P.; DeKoster, G. T.; Cistola, D. P.; Covey, D. F.. Synthesis of [3, 4-13C2]-Enriched Bile Salts as NMR Probes of Protein-Ligand Interactions. J. Org. Chem.,2002,67(19),6764-6771.
[70]Zhang, H. Y.; Qiu, Z. B.. An efficient synthesis of 5a-androst-l-ene-3,17-dione. Steroids.,2006,71(13-14),1088-1090.
[71]Aranda, G.; Fetizon, M.; Tayeb, N.. Synthese d'antibiotiques triterpeniques a partir d'acides biliaires:IV. Etude de 1'hydrogenation catalytique du dimethyl-4,4 cholene-5 one-3 oate-24 de methyle. Tetrahedron,1987,43 (18), 4147-4157.
[72]Corey, E. J.; Venkateswarlu, A.. Protection of Hydroxyl Groups as tert-Butyldimethylsilyl Derivatives. J.Am.Chem.Soc.,1972,94 (17),6190-6191.
[73]Ibrahim-Ouali, M.; Hamze, K.; Rocheblave, L.. Synthesis of 12-oxa,12-aza and 12-thia cholanetriols. Steroids,2011,76 (3),324-330.
[74]Taotafa, U.; McMullin, D. B.; Lee, S. C.; Hansen, L. D.; Savage, P. B.. Anionic Facial Amphiphiles from Cholic Acid. Org. Lett.,2000,2 (26),4117-4120.
[75]Frincke; James, M.. drugs and uses. WO2008039566.
[76]Kelly, D. R.; Roberts, S. M.; Newton, R. F.. The cleavage of tert-butyldimethylsilyl ethers with boron trifluoride etherate. Synth. Commun., 1979,9 (4),295-299.
[77]King, S. A.; Pipik, B.; Thompson, A. S.; DeCamp, A.; Verhoeven, T. R.. Efficient synthesis of carbapenems via the oxalimide cyclization. Manipulation of protecting groups at the oxalimide stage. Tetrahedron Lett.,1995,36(26), 4563-4566.
[78]Bou, V.; Vilarrasa, J.. New synthetic tricks. Trimethylsilyl triflate mediated cleavage of hindered silyl ethers. Tetrahedron Lett.,1990,31(4),567-568.
[79]Ono, Y.; Kawase, A.; Watanabe, H.; Shiraishi, A.; Takeda, S.; Higuchi, Y.; Sato, K.; Yamauchi, T.; Mikami, T.; Kato, M.; Tsugawa, N.; Okano, T.; Kubodera, N.. Syntheses and preventive effects of analogues related to lalpha, 25-dihydroxy-2beta-(3-hydroxypropoxy)vitamin D3 (ED-71) on bone mineral loss in ovariectomized rats. Bioorg. Med. Chem.,1998,6(12),2517-2523.
[80]Lotowski, Z.; Kulesza, U.. Studies on the synthesis of cholane derivatives containing a mercapto group and their dimers with disulfide spacers. Part 1. 24-Mercapto-5β-cholane-3a,7a,12a-triol and its C(24)-C(24') disulfide dimmer. Journal of Sulfur Chemistry,2010,31 (2),97-102.
[81]Ma, S. M.; Li, J. W.; Choi, J. W.; Zhou, H.; Lee, K. K.; Moorthie, V. A.; Xie, X.; Kealey, J. T.; Da Silva, N. A.; Vederas, J. C.; Tang, Y.. Complete Reconstitution of a Highly Reducing Iterative Polyketide Synthase. Science, 2009,326(5952),589-592.
[82]Klett, E. L.; Lee, M. H.; Adams, D. B.; Chavin, K. D.; Patel, S. B.. Localization of ABCG5 and ABCG8 proteins in human liver, gall bladder and intestine. BMC Gastroenterol,2004,4(1),21-27.
[83]罗建学,李春风,初晓辉,谷大海,黎小青,徐志强。脂肪酸合成酶基因的研究进展。中国畜牧兽医,2011,38(6),118-121。
[84]Burbaum, J.; Tobal, G. M.. Proteomics in drug discovery. Curr. Opin. Chem. Biol,2002,6 (4), 427-433.
[85]仇文卫,汤杰.化学小分子探针在药物发现中的应用.化学教学，2009,(9),1-4.
[86]Jeffery, D. A.; Bogyo, M.. Chemical proteomics and its application to drug discovery. Curr. Opin. Biotechnol,2003,14 (1),87-95.
[87]张煚,周虎臣.小分子探针在确定活性化合物的生物靶点中的应用.药学学报，2012,47例,299-306.
[88]Singh, A.; Thornton, E. R.; Westheimer, F. H.. The photolysis of diazoacetyl-chymotrypsin. J. Biol. Chem.,1962,237,3006-3008.
[89]Brunner, J.; Senn, H.; Richards, F. M..3-Trifluoromethyl-3-phenyldiazirine. A new carbene generating group for photolabeling reagents. J. Biol. Chem.,1980, 255(8),3313-3318.
[90]Fleet, G. W. J.; Porter, R. R.; Knowles, J. R.. Affinity labeling of antibodies with aryl nitrene as reactive group. Nature(London),1969,224,511-512.
[91]Hatanaka, Y., Sadakane, Y.. Photoaffinity Labelling in Drug Discovery and Developments:Chemistry Gateway for Entering Proteomic Frontier, Curr. Top. Med. Chem.,2002,2 (3),271-288.
[92]仇文卫,李静雅,李佳,南发俊.光亲和标记技术在药物发现中的应用.生命科学2005,17(4),296-303.
[93]Shiyama, T.; Furuya, M.; Yamazaki, A.; Terada, T.; Tanaka, A.. Design and synthesis of novel hydrophilic spacers for the reduction of nonspecific binding proteins on affinity resins. Bioorg. Med. Chem.,2004,12 (11),2831-2841.
[94]Borodovsky, A.; Ovaa, H.; Kolli, N.; Gan-Erdene, T.; Wilkinson, K. D.; Ploegh, H. L.; Kessler, B.M.. Chemistry-Based Functional Proteomics Reveals Novel Members of the Deubiquitinating Enzyme Family. Chem. Biol.2002,9 (10), 1149-1159.
[95]Jiarpinitnun, C; Kiessling, L. L.. Unexpected Enhancement in Biological Activity of a GPCR Ligand Induced by an Oligoethylene Glycol Substituent. J. Am. Chem. Soc.,2010,132 (26),8844-8845.
[96]Sato, S.; Murata, A.; Shirakawa, T. Uesuqi, M.. Biochemical target isolation for novices:affinity-based strategies. Chem. Biol,2010,17(6),616-623.
[97]Sato, S.; Kwon, Y.; Kamisuki, S.; Srivastava, N.; Mao, Q.; Kawazoe, Y.; Uesugi, M.. Polyproline-rod approach to isolating protein targets of bioactive small molecules:isolation of a new target of indomethacin. J. Am. Chem. Soc., 2007,129(4),873-880.
[98]Rappsiber, J.; Mann, M.. What dose it mean to identify a protein in proteomics? Trends. Biochem. Sci.,2007,27(2),74-78.
[99]顾民.茉莉素/类茉莉素小分子探针的设计、合成及应用.华东师范大学研究生博士学位论文.2012.
[100]Wilchek, M.; Bayer, E. A.. Introduction to avidin-biotin technology. Methods. Enzymol.,1990,184,5-13.
[101]Nassal, M..4'-(1-Azi-2,2,2-trifluoroethyl)phenylalanine, a photolabile carbene-generating analog of phenylalanine. J. Am. Chem. Soc.,1984,106 (24), 7540-7545.
[102]Hatanaka, Y.; Yoshida, E.; Nakayama, H.; Kanaoka, Y.. Chromogenic diazirine: A new spectrophotometric approach for photoaffinity labeling. Bioorg. Chem., 1989,17(4),482-485.
[103]Hatanaka, Y.; Kempin, U.; Jong-Jip, P.. One-step synthesis of biotinyl photoprobes from unprotected carbohydrates. J. Org. Chem.,2000,65 (18), 5639-5643.
[104]Allin, S. M.; Barton, W. R. S.; Bowman, W. R.; Bridge (nee Mann), E.; Elsegood, M. R. J.; McInally, T.; McKee, V.. Bu3SnH-mediated radical cyclisation onto azoles. Tetrahedron,2008,64 (33),7745-7758.
[105]Kawakami, Y.; Kitani, H.; Yuasa, S.; Abe, M; Moriwaki, M.; Kagoshima, M.; Terasawa, M.; Tahara, T.. Structural optimization of 4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepines as antagonists for platelet activating factor:pharmacological contribution of substituents at the 2-and 6-positions of a condensed ring system.Eur. J. Med. Chem.,1996,31 (9), 683-692.
[106]Tewari, A. K.; Dubey, R.; Mishra, A..2-Substituted-8-methyl-3,6-Dihy-Droimidazo[4,5-c] pyrazolo[3,4-e] pyridazine as an anti-inflammatory agent. Med. Chem. Res.,2011,20,125-129.
[107]Wei, C. X.; Deng, X. Q.; Chai, K. Y.; Sun, Z. G.; Quan, Z. S.. Synthesis and anticonvulsant activity of 1-formamide-triazolo[4,3-a]quinoline derivatives. Arch. Pharm. Res.,2010,33 (5),655-662.
[108]Gitto, R.; Orlando, V.; Quartarone, S.; De Sarro, G.; De Sarro, A.; Russo, E.; Ferreri, G.; Chimirri, A.. Synthesis and evaluation of pharmacological properties of novel annelated 2,3-benzodiazepine derivatives. J. Med. Chem., 2003,46(17),3758-3761.
[109]Hassan, S. Y.. Synthesis and Biological Activity of Some New Pyrazoline and Pyrimidine Derivatives. J. Braz. Chem. Soc.,2011,22 (7),1286-1298.
[110]Masuda, S.; Tomohiro, T.; Hatanaka, Y.. Rapidly photoactivatable ATP probes for specific labeling of tropomyosin within the actomyosin protein complex. Bioorg. Med. Chem. Lett.,2011,21 (8),2252-2254.
[111]Fujiwara, T.; Hirashima, N.; Hasegawa, S.; Nakanishi, M.; Ohwada, T. Space-filling effects in membrane disruption by cationic amphiphiles. Bioorg. Med. Chem.2001,9 (4),1013-1024.
[112]Nahar, L.; Turner, A. B.. Synthesis of ester-linked lithocholic acid dimmers. Steroids,2003,68 (14),1157-1161.
[113]杨红文。三氧化铬二吡啶、三氧化铬吡啶盐酸盐-两种有效的专用氧化剂。化学研究与应用,2000,12(1),74-76.
[114]Tohma, M.; Mahara, R.; Takeshita, H.; Kurosawa, T.. A convenient synthesis of 3β,12α-,3β,7α-, and 3β,7β-dihydroxy-5-cholen-24-oic acids:Unusual bile acids in human biological fluids. Steriods,1986,48 (5-6),331-338.
[115]Iida T, Shiraishi K, Ogawa S, Goto T, Mano N, Goto J, Nambara T. Functionalization of unactivated carbons in 3 alpha,6- and 3 alpha, 24-dihydroxy-5beta-cholane derivatives by dimethyldioxirane. Lipids.,2003, 38(3),281-287.
[116]Ibrahim-Ouali, M.; Rocheblave, L.. First synthesis of thia steroids from cholic acid. Steroids,2010,75 (10),701-709.
[117]Hatanaka, Y; Hashimoto, M; Kanaoka, Y.. A novel biotinylated heterobifunctional cross-linking reagent bearing an aromatic diazirine. Bioorg. Med. Chem.,1994,2(12),1367-1373.
[118]Hashimoto, M; Hatanaka, Y; Yang, J; Dhesi, J; Holman, G. D.. Synthesis of biotinylated bis(D-glucose) derivatives for glucose transporter photoaffinity labeling. Carbohydr. Res.,2001,331(2),119-127.
[119]Kan, T; Kita, Y; Morohashi, Y; Tominari, Y; Hosoda, S; Tomita, T; Natsugari, H; Iwatsubo, T; Fukuyama, T.. Convenient synthesis of photoaffinity probes and evaluation of their labeling abilities. Org. Lett.,2007,9(11),2055-2058.
[2]Casserly, I. P.; Topol, E. J.. Convergence of atherosclerosis and alzheimer's disease:Cholesterol, inflammation, and misfolded proteins. Discov. Med.,2004, 4(22),149-156.
[3]Lewington, S.; Whitlock, G..;, Clarke, R.; Sherliker, P.; Emberson, J.; Halsey, J.; Qizilbash, N.; Peto, R.; Collins, R.. Blood cholesterol and vascular mortality by age, sex, and blood pressure:a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet,2007,370 (9602), 1829-1839.
[4]Murray, C. J.; Lauer, J. A.; Hutubessy, R. C.; Niessen, L.; Tomijima, N.; Rodgers, A.; Lawes, C. M.; Evans, D. B.. Effectiveness and costs of interventions to lower systolic blood pressure and cholesterol:a global and regional analysis on reduction of cardiovascular-disease risk. Lancet,2003,361 (9359),717-725.
[5]Keys, A.. Coronary heart disease-the global picture. Atherosclerosis,1975,22 (2),149-192.
[6]Fonseca, A. C.; Resende, R.; Oliveira, C. R.; Pereira, C. M.. Cholesterol and statins in Alzheimer's disease:current controversies. Exp. Neurol,2010,223 (2), 282-293.
[7]Wolozin, B.. Cholesterol and the biology of Alzheimer's disease. Neuron,2004, 41(1),7-10.
[8]Wang, H. H.; Portincasa, P.; Mendez-Sanchez, N.; Uribe, M.; Wang, D. Q.. Effect of ezetimibe on the prevention and dissolution of cholesterol gallstones. Gastmenterology,2008,134 (7),2101-2110.
[9]王卫珍.他汀类降脂药的药理作用和应用指导.中华临床医学研究杂志2007,13(15),2243-2244.
[10]骆雷鸣,刘果树.他汀类药物的临床药理和应用.药物不良反应(ADRJ)2001,(3),145-150.
[11]Goldstein, J. L.; Brown, M. S.. Regulation of the mevalonate pathway. Nature, 1990,343 (6257),425-430.
[12]Gil, G.; Faust, J. R.; Chin, D. J.; Goldstein, J. L.; Brown, M. S.. Membrane-bound domain of HMG CoA reductase is required for sterol-enhanced degradation of the enzyme. Cell,1985,41 (1),249-258.
[13]Roitelman, J.; Olender, E. H.; Bar-Nun, S.; Dunn, WA. Jr.; Simoni, R. D.. Immunological evidence for eight spans in the membrane domain of 3-hydroxy-3-methylglutaryl coenzyme A reductase:implications for enzyme degradation in the endoplasmic reticulum. J. Cell Biol,1992,117 (5),959-973.
[14]左玉,冯丽霞,魏世芳。胆固醇的研究及应用。太原师范学院学报(自然科学版),2010，9(4)，104-107.
[15]Brown, M. S.; Goldstein, J. L.. The SREBP pathway:regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell, 1997,89 (3),331-340.
[16]郭晓强,郭振清SREBP介导的胆固醇生物合成反馈调节.(?)Chemistry Of Life, 2007,27 (4),292-294.
[17]Kim, J. B.; Spiegelman, B. M.. ADD1/SREBP1 promotes adipocyte differentiation and gene expression linked to fatty acid metabolism. Genes. Dev.,1996,10 (9),1096-1107.
[18]Osborne, T. F.. Transcriptional control mechanisms in the regulation of cholesterol balance. Crit. Rev. Eukaryot. Gene Expr.,1995,5 (3-4),317-335.
[19]Ericsson, J.; Jackson, S. M.; Edwards, P. A.. Synergistic binding of sterol regulatory element-binding protein and NF-Y to the farnesyl diphosphate synthase promoter is critical for sterol-regulated expression of the gene. J. Biol. Chem.1996,271 (40),24359-24364.
[20]Magana, M. M.; Osborne, T. F.. Two tandem binding sites for sterol regulatory element binding proteins are required for sterol regulation of fatty-acid synthase promoter. J Biol Chem,1996,271 (51),32689-32694.
[21]Oliner, J. D.; Andresen, J. M.; Hansen, S. K.; Zhou, S.; Tjian, R.. SREBP transcriptional activity is mediated through an interaction with the CREB-binding protein. Genes Dev,1996,10 (22),2903-2911.
[22]Rawson, R. B.. Control of lipid metabolism by regulated intramembrane proteolysis of sterol regulatory element binding proteins (SREBPs). Biochem. Soc. Symp.,2003, (70),221-231.
[23]Takahata, R.; Matsumtlra, H.; Kantha, S. S.; Kubo, E.; Kawase, K.; Sakai, T.; Hayaishi, O.. Intravenous administration of inorganic selenium compounds, inhibitors of prostaglandin D synthase, inhibits sleep in freely moving rats. Brain Res,1993,623 (1),65-71.
[24]Steck, T. L.; Lange, Y.. SCAP, an ER sensor that regulates cell cholesterol. Dev Cell,2002,3 (3),306-308.
[25]Adams, C. M.; Reitz, J.; De Brabander, J. K.; Feramisco, J. D.; Li, L.; Brown, M. S.; Goldstein, J. L.. Cholesterol and 25-hydroxycholesterol inhibit activation of SREBPs by different mechanisms, both involving SCAP and insigs. J. Biol. Chem.,2004,279 (50),52772-52780.
[26]Brown, A. J.; Sun, L.; Feramisco, J. D.; Brown, M. S.; Goldstein, J. L. Cholesterol addition to ER membranes alters conformation of SCAP, the SREBP escort protein that regulates cholesterol metabolism. Mol. Cell.,2002, 10(2),237-245.
[27]Adams, C. M.; Goldstein, J. L.; Brown, M. S.. Cholesterol-induced conformational change in SCAP enhanced by Insig proteins and mimicked by cationic amphiphiles. Proc. Natl. Acad. Sci. USA,2003,100 (19), 10647-10652.
[28]Bucher, N. L.; Overath, P.; Lynen, F.. β-Hydroxy-(3-methylglutaryl coenzyme A reductase, cleavage and condensing enzymes in relation to cholesterol formation in rat liver. Biochim Biophys Acta,1960,40,491-501.
[29]Siperstein, M. D.; Fagan, V. M.. Feedback control of mevalonate synthesis by dietary cholesterol. J Biol Chem,1966,241 (3),602-609.
[30]Sever, N.; Song, B. L.; Yabe, D.; Goldstein, J. L.; Brown, M. S.; DeBose-Boyd, R.A.Jnsig-dependent ubiquitination and degradation of mammalian 3-hydroxy-3-methylglutaryl-Co A reductase stimulated by sterols and geranylgeraniol. J. Biol. Chem.,2003,278 (52),52479-52490.
[31]Sever, N.; Yang, T.; Brown, M. S.; Goldstein, J. L.; DeBose-Boyd, R. A.. Accelerated degradation of HMGCoA reductase mediated by binding of insig-1 to its sterol-sensing domain. Mol. Cell,2003,11 (1),25-33.
[32]Brown, M. S.; Goldstein, J. L.. A receptor-mediated path way for cholesterol homeostasis. Science,1986,232 (4746),34-41.
[33]Kajinami, K.; Takekoshi, N.. Cholesterol absorption inhibitors in development as potential therapeutics. Expert. Opin. Investig. Drugs.,2002,11 (6),831-835.
[34]Miettinen, T. A.. Cholesterol absorption inhibition:a strategy for cholesterol-lowering therapy. Int. J. Clin. Pract,2001,55 (10),710-716.
[35]Ge, L.; Qi, W.; Wang, L. J.; Miao, H. H.; Qu, Y. X.; Li, B. L.; Song, B. L. Flotillins play an essential role in Niemann-Pick Cl-like 1-mediated cholesterol uptake. Proc. Nat.l Acad. Sci. USA.,2011,108 (2),551-556.
[36]Knopp, R. H.; Gitter, H.; Truitt, T.; Bays, H.; Manion, C. V.; Lipka, L. J.; LeBeaut, A. P.; Suresh, R.; Yang, B.; Veltri, E. P.. Effects of ezetimibe, a new cholesterol absorption inhibitor,on plasma lipids in patients with primary hypercholesterolemia. Eur. Heart J.,2003,24 (8),729-741.
[37]Mitka, M.. Cholesterol drug controversy continues. JAMA,2008,299 (19), 2266.
[38]Taylor, A. J.; Villines, T. C.; Stanek, E. J.; Devine, P.; Griffen, L.; Miller, M.; Weissman, N. J.; Turco, M.. Extended-release niacin or ezetimibe and carotid intima-media thickness. N. Engl. J. Med.,2009,361 (22),2113-2122.
[39]付春.降血脂手性新药伊泽替米得合成,2007, (5),29-31.
[40]Ballantyne, C. M.; Olsson, A.G.; Cook, T. J.; Mercuri, M. F.; Pedersen, T. R.; Kjekshus, J.. Influence of low high-density Lipoprotein cholesterol and elevated triglyceride on coronary heart disease events and response to simvastatin therapy in 4S. Circulaion,2001,104 (25),3046-3051.
[41]Kastelein, J. J.; Akdim, F.; Stroes, E. S.; Zwinderman, A. H.; Bots, M. L.; Stalenhoef, A. F.; Visseren, F. L.; Sijbrands, E. J.; Trip, M. D.; Stein, E. A.; Gaudet, D.; Duivenvoorden, R.; Veltri, E. P.; Marais, A. D.; de Groot, E.. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N. Engl. J. Med.,2008,358 (14),1431-1443.
[42]Negredo, E.; Molto, J.; Puig, J.; Cinquegrana, D.; Bonjoch, A.; Perez-Alvarez, N.; Lopez-Blazquez, R.; Blanco, A.; Clotet, B.; Rey-Joly, C. Ezetimibe, a promising lipid-lowering agent for the treatment of dyslipidaemia in HIV infected patients with poor response to statins. AIDS.,2006,20 (17), 2159-2164.
[43]Giandomenico, V.; Simonsson, M.; Gronroos, E.; Ericsson, J.. Coactivator-dependent acetylation stabilizes members of the SREBP family of transcription factors. Mol. Cell. Biol,2003,23 (7),2587-2599.
[44]Anderson, R. G.. Joe Goldstein and Mike Brown:from cholesterol homeostasis to new paradigms in membrane biology. Trends. Cell. Biol,2003,13 (10), 534-539.
[45]Maron, D. J.; Fazio, S.; Linton, M.F.. Current perspectives on stains. Circulation,2000,101 (2),207-213.
[46]陈明卫,杨明功。他汀类药物肌毒性及其他毒副反应的发现与警惕.实用糖尿病杂志，2005,1(4)，13-15.
[47]Law, M. R.; Wald, N. J.; Rudnicka, A. R.. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke:systematic review and meta-analysis. BMJ,2003,326 (7404),1423.
[48]Thompson, P. D.; Clarkson, P.; Karas, R. H.. Statin-associated myopathy. JAMA.,2003,289 (13),1681-1690.
[49]Roberts, W. C. The underused miracle drugs:the statin drugs are to atherosclerosis what penicillin was to infectious disease. Am. J. Cardiol,1996,78 (3),377-378
[50]Topol, E. J.. Intensive statin therapy--a sea change in cardiovascular prevention. N.Engl.J.Med.,2004,350 (15),1562-1564.
[51]Kiortsis, D. N.; Filippatos, T. D.; Mikhailidis, D. P.; Elisaf, M. S.; Liberopoulos, E. N.. Statin-associated adverse effects beyond muscle and liver toxicity. Atherosclerosis,2007,195 (1),7-16.
[52]Vasudevan, A. R.; Hamirani, Y. S.; Jones, P. H., Safety of statins:effects on muscle and the liver. Cleve. Clin. J. Med.,2005,72(11),990-993,996-1001.
[53]Farmer, J. A.. Learning from the cerivastatin experience. Lancet,2001,358 (9291),1383-1385.
[54]Editorial. The statin wars:why AstraZeneca must retreat. Lancet,2003,362 (9393),1341.
[55]DeBose-Boyd, R. A.2009,25,206.1.
[56]Song, B. L.; DeBose-Boyd, R. A.. Ubiquitination of 3-hydroxy-3-methylglutaryl-CoA reductase in permeabilized cells mediated by cytosolic E1 and a putative membrane-bound ubiquitin ligase. J. Biol. Chem., 2004,279 (27),28798-28806.
[57]Song, B. L.; Javitt, N. B.; DeBose-Boyd, R. A.. Insig-mediated degradation of HMG CoA reductase stimulatedby lanosterol, an intermediate in the synthesis of cholesterol. Cell. Metab.,2005,1 (3),179-189.
[58]Horton, J. D.; Shimomura, I.. Sterol regulatory element-binding proteins: activators of cholesterol and fatty acid biosynthesis. Curr. Opin. Lipidol.,1999, 10,143-150.
[59]Repa, J. J.; Mangelsdorf, D. J.. The role of orphan nuclear receptors in the regulation of cholesterol homeostasis. Annu. Rev. Cell. Dev. Biol,2000,16, 459-481.
[60]Venkateswaran, A.; Laffitte, B. A.; Joseph, S. B.; Mak, P. A.; Wilpitz, D. C.; Edwards, P. A.; Tontonoz, P.. Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXR. Proc. Natl. Acad. Sci. USA.,2000,97 (22), 12097-12102.
[61]Repa, J. J.; Mangelsdorf, D. J.. The liver X receptor gene team:potential new players in atherosclerosis. Nat. Med.,2002,8 (11),1243-1248.
[62]Peet, D. J.; Turley, S. D.; Ma, W.; Janowski, B. A.; Lobaccaro, J. M.; Hammer, R. E.; Mangelsdorf, D. J.. Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxy sterol receptor LXR alpha. Cell,1998,93 (5), 693-704.
[63]Repa, J. J.; Liang, G.; Ou, J.; Bashmakov, Y.; Lobaccaro, J. M.; Shimomura, I.; Shan, B.; Brown M, S.; Goldstein, J. L.; Mangelsdorf, D. J.. Regulation of mouse sterol regulatory element-binding protein-lc gene (SREBP-1c) by oxysterol receptors, LXRal-pha and LXRbeta. Genes. Dev.,2000,14 (22), 2819-2830.
[64]Joseph, S. B.; McKilligin, E.; Pei, L.; Watson, M. A.; Collins, A. R.; Laffitte, B. A.; Chen, M.; Noh, G.; Goodman, J.; Hagger, G. N.; Tran, J.; Tippin, T. K.; Wang, X.; Lusis, A. J.; Hsueh, W. A.; Law, R. E.; Collins, J. L.; Willson, T. M.; Tontonoz, P.. Synthetic LXR ligand inhibits the development of atherosclerosis in mice. Proc. Natl. Acad. Sci. USA.,2002,99 (11),7604-7609.
[65]Tang, J. J.; Li, J. G.; Qi, W.; Qiu, W. W.; Li, P. S.; Li, B. L.; Song, B. L. Inhibition of SREBP by a Small Molecule, Betulin,Improves Hyperlipidemia and Insulin Resistanceand Reduces Atherosclerotic Plaques. Cell. Metab., 2011,13 (1),44-56.
[66]Dang, Z.; Lin, A.; Ho, P.; Soroka, D.; Lee, K. H.; Huang, L.; Chen, C. H.. Synthesis and proteasome inhibition of lithocholic acid derivatives. Bioorg. Med. Chem. lett.,2011,21(7),1926-1928.
[67]Mizushina, Y.; Kasai, N.; Miura, K.; Hanashima, S.; Takemura, M.; Yoshida, H.; Sugawara, F.; Sakaguchi, K.. Structural relationship of lithocholic acid derivatives binding to the N-terminal 8-kDa domain of DNA polymerase beta. Biochemistry.,2004,43(33),10669-10677.
[68]Goldberg, A. A.; Beach, A.; Davies, G. F.; Harkness, T. A.; Leblanc, A.; Titorenko, V. I.. Lithocholic bile acid selectively kills neuroblastoma cells, while sparing normal neuronal cells. Oncotarget.,2011,2(10),761-782.
[69]Tochtrop, G. P.; DeKoster, G. T.; Cistola, D. P.; Covey, D. F.. Synthesis of [3, 4-13C2]-Enriched Bile Salts as NMR Probes of Protein-Ligand Interactions. J. Org. Chem.,2002,67(19),6764-6771.
[70]Zhang, H. Y.; Qiu, Z. B.. An efficient synthesis of 5a-androst-l-ene-3,17-dione. Steroids.,2006,71(13-14),1088-1090.
[71]Aranda, G.; Fetizon, M.; Tayeb, N.. Synthese d'antibiotiques triterpeniques a partir d'acides biliaires:IV. Etude de 1'hydrogenation catalytique du dimethyl-4,4 cholene-5 one-3 oate-24 de methyle. Tetrahedron,1987,43 (18), 4147-4157.
[72]Corey, E. J.; Venkateswarlu, A.. Protection of Hydroxyl Groups as tert-Butyldimethylsilyl Derivatives. J.Am.Chem.Soc.,1972,94 (17),6190-6191.
[73]Ibrahim-Ouali, M.; Hamze, K.; Rocheblave, L.. Synthesis of 12-oxa,12-aza and 12-thia cholanetriols. Steroids,2011,76 (3),324-330.
[74]Taotafa, U.; McMullin, D. B.; Lee, S. C.; Hansen, L. D.; Savage, P. B.. Anionic Facial Amphiphiles from Cholic Acid. Org. Lett.,2000,2 (26),4117-4120.
[75]Frincke; James, M.. drugs and uses. WO2008039566.
[76]Kelly, D. R.; Roberts, S. M.; Newton, R. F.. The cleavage of tert-butyldimethylsilyl ethers with boron trifluoride etherate. Synth. Commun., 1979,9 (4),295-299.
[77]King, S. A.; Pipik, B.; Thompson, A. S.; DeCamp, A.; Verhoeven, T. R.. Efficient synthesis of carbapenems via the oxalimide cyclization. Manipulation of protecting groups at the oxalimide stage. Tetrahedron Lett.,1995,36(26), 4563-4566.
[78]Bou, V.; Vilarrasa, J.. New synthetic tricks. Trimethylsilyl triflate mediated cleavage of hindered silyl ethers. Tetrahedron Lett.,1990,31(4),567-568.
[79]Ono, Y.; Kawase, A.; Watanabe, H.; Shiraishi, A.; Takeda, S.; Higuchi, Y.; Sato, K.; Yamauchi, T.; Mikami, T.; Kato, M.; Tsugawa, N.; Okano, T.; Kubodera, N.. Syntheses and preventive effects of analogues related to lalpha, 25-dihydroxy-2beta-(3-hydroxypropoxy)vitamin D3 (ED-71) on bone mineral loss in ovariectomized rats. Bioorg. Med. Chem.,1998,6(12),2517-2523.
[80]Lotowski, Z.; Kulesza, U.. Studies on the synthesis of cholane derivatives containing a mercapto group and their dimers with disulfide spacers. Part 1. 24-Mercapto-5β-cholane-3a,7a,12a-triol and its C(24)-C(24') disulfide dimmer. Journal of Sulfur Chemistry,2010,31 (2),97-102.
[81]Ma, S. M.; Li, J. W.; Choi, J. W.; Zhou, H.; Lee, K. K.; Moorthie, V. A.; Xie, X.; Kealey, J. T.; Da Silva, N. A.; Vederas, J. C.; Tang, Y.. Complete Reconstitution of a Highly Reducing Iterative Polyketide Synthase. Science, 2009,326(5952),589-592.
[82]Klett, E. L.; Lee, M. H.; Adams, D. B.; Chavin, K. D.; Patel, S. B.. Localization of ABCG5 and ABCG8 proteins in human liver, gall bladder and intestine. BMC Gastroenterol,2004,4(1),21-27.
[83]罗建学,李春风,初晓辉,谷大海,黎小青,徐志强。脂肪酸合成酶基因的研究进展。中国畜牧兽医,2011,38(6),118-121。
[84]Burbaum, J.; Tobal, G. M.. Proteomics in drug discovery. Curr. Opin. Chem. Biol,2002,6 (4), 427-433.
[85]仇文卫,汤杰.化学小分子探针在药物发现中的应用.化学教学，2009,(9),1-4.
[86]Jeffery, D. A.; Bogyo, M.. Chemical proteomics and its application to drug discovery. Curr. Opin. Biotechnol,2003,14 (1),87-95.
[87]张煚,周虎臣.小分子探针在确定活性化合物的生物靶点中的应用.药学学报，2012,47例,299-306.
[88]Singh, A.; Thornton, E. R.; Westheimer, F. H.. The photolysis of diazoacetyl-chymotrypsin. J. Biol. Chem.,1962,237,3006-3008.
[89]Brunner, J.; Senn, H.; Richards, F. M..3-Trifluoromethyl-3-phenyldiazirine. A new carbene generating group for photolabeling reagents. J. Biol. Chem.,1980, 255(8),3313-3318.
[90]Fleet, G. W. J.; Porter, R. R.; Knowles, J. R.. Affinity labeling of antibodies with aryl nitrene as reactive group. Nature(London),1969,224,511-512.
[91]Hatanaka, Y., Sadakane, Y.. Photoaffinity Labelling in Drug Discovery and Developments:Chemistry Gateway for Entering Proteomic Frontier, Curr. Top. Med. Chem.,2002,2 (3),271-288.
[92]仇文卫,李静雅,李佳,南发俊.光亲和标记技术在药物发现中的应用.生命科学2005,17(4),296-303.
[93]Shiyama, T.; Furuya, M.; Yamazaki, A.; Terada, T.; Tanaka, A.. Design and synthesis of novel hydrophilic spacers for the reduction of nonspecific binding proteins on affinity resins. Bioorg. Med. Chem.,2004,12 (11),2831-2841.
[94]Borodovsky, A.; Ovaa, H.; Kolli, N.; Gan-Erdene, T.; Wilkinson, K. D.; Ploegh, H. L.; Kessler, B.M.. Chemistry-Based Functional Proteomics Reveals Novel Members of the Deubiquitinating Enzyme Family. Chem. Biol.2002,9 (10), 1149-1159.
[95]Jiarpinitnun, C; Kiessling, L. L.. Unexpected Enhancement in Biological Activity of a GPCR Ligand Induced by an Oligoethylene Glycol Substituent. J. Am. Chem. Soc.,2010,132 (26),8844-8845.
[96]Sato, S.; Murata, A.; Shirakawa, T. Uesuqi, M.. Biochemical target isolation for novices:affinity-based strategies. Chem. Biol,2010,17(6),616-623.
[97]Sato, S.; Kwon, Y.; Kamisuki, S.; Srivastava, N.; Mao, Q.; Kawazoe, Y.; Uesugi, M.. Polyproline-rod approach to isolating protein targets of bioactive small molecules:isolation of a new target of indomethacin. J. Am. Chem. Soc., 2007,129(4),873-880.
[98]Rappsiber, J.; Mann, M.. What dose it mean to identify a protein in proteomics? Trends. Biochem. Sci.,2007,27(2),74-78.
[99]顾民.茉莉素/类茉莉素小分子探针的设计、合成及应用.华东师范大学研究生博士学位论文.2012.
[100]Wilchek, M.; Bayer, E. A.. Introduction to avidin-biotin technology. Methods. Enzymol.,1990,184,5-13.
[101]Nassal, M..4'-(1-Azi-2,2,2-trifluoroethyl)phenylalanine, a photolabile carbene-generating analog of phenylalanine. J. Am. Chem. Soc.,1984,106 (24), 7540-7545.
[102]Hatanaka, Y.; Yoshida, E.; Nakayama, H.; Kanaoka, Y.. Chromogenic diazirine: A new spectrophotometric approach for photoaffinity labeling. Bioorg. Chem., 1989,17(4),482-485.
[103]Hatanaka, Y.; Kempin, U.; Jong-Jip, P.. One-step synthesis of biotinyl photoprobes from unprotected carbohydrates. J. Org. Chem.,2000,65 (18), 5639-5643.
[104]Allin, S. M.; Barton, W. R. S.; Bowman, W. R.; Bridge (nee Mann), E.; Elsegood, M. R. J.; McInally, T.; McKee, V.. Bu3SnH-mediated radical cyclisation onto azoles. Tetrahedron,2008,64 (33),7745-7758.
[105]Kawakami, Y.; Kitani, H.; Yuasa, S.; Abe, M; Moriwaki, M.; Kagoshima, M.; Terasawa, M.; Tahara, T.. Structural optimization of 4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepines as antagonists for platelet activating factor:pharmacological contribution of substituents at the 2-and 6-positions of a condensed ring system.Eur. J. Med. Chem.,1996,31 (9), 683-692.
[106]Tewari, A. K.; Dubey, R.; Mishra, A..2-Substituted-8-methyl-3,6-Dihy-Droimidazo[4,5-c] pyrazolo[3,4-e] pyridazine as an anti-inflammatory agent. Med. Chem. Res.,2011,20,125-129.
[107]Wei, C. X.; Deng, X. Q.; Chai, K. Y.; Sun, Z. G.; Quan, Z. S.. Synthesis and anticonvulsant activity of 1-formamide-triazolo[4,3-a]quinoline derivatives. Arch. Pharm. Res.,2010,33 (5),655-662.
[108]Gitto, R.; Orlando, V.; Quartarone, S.; De Sarro, G.; De Sarro, A.; Russo, E.; Ferreri, G.; Chimirri, A.. Synthesis and evaluation of pharmacological properties of novel annelated 2,3-benzodiazepine derivatives. J. Med. Chem., 2003,46(17),3758-3761.
[109]Hassan, S. Y.. Synthesis and Biological Activity of Some New Pyrazoline and Pyrimidine Derivatives. J. Braz. Chem. Soc.,2011,22 (7),1286-1298.
[110]Masuda, S.; Tomohiro, T.; Hatanaka, Y.. Rapidly photoactivatable ATP probes for specific labeling of tropomyosin within the actomyosin protein complex. Bioorg. Med. Chem. Lett.,2011,21 (8),2252-2254.
[111]Fujiwara, T.; Hirashima, N.; Hasegawa, S.; Nakanishi, M.; Ohwada, T. Space-filling effects in membrane disruption by cationic amphiphiles. Bioorg. Med. Chem.2001,9 (4),1013-1024.
[112]Nahar, L.; Turner, A. B.. Synthesis of ester-linked lithocholic acid dimmers. Steroids,2003,68 (14),1157-1161.
[113]杨红文。三氧化铬二吡啶、三氧化铬吡啶盐酸盐-两种有效的专用氧化剂。化学研究与应用,2000,12(1),74-76.
[114]Tohma, M.; Mahara, R.; Takeshita, H.; Kurosawa, T.. A convenient synthesis of 3β,12α-,3β,7α-, and 3β,7β-dihydroxy-5-cholen-24-oic acids:Unusual bile acids in human biological fluids. Steriods,1986,48 (5-6),331-338.
[115]Iida T, Shiraishi K, Ogawa S, Goto T, Mano N, Goto J, Nambara T. Functionalization of unactivated carbons in 3 alpha,6- and 3 alpha, 24-dihydroxy-5beta-cholane derivatives by dimethyldioxirane. Lipids.,2003, 38(3),281-287.
[116]Ibrahim-Ouali, M.; Rocheblave, L.. First synthesis of thia steroids from cholic acid. Steroids,2010,75 (10),701-709.
[117]Hatanaka, Y; Hashimoto, M; Kanaoka, Y.. A novel biotinylated heterobifunctional cross-linking reagent bearing an aromatic diazirine. Bioorg. Med. Chem.,1994,2(12),1367-1373.
[118]Hashimoto, M; Hatanaka, Y; Yang, J; Dhesi, J; Holman, G. D.. Synthesis of biotinylated bis(D-glucose) derivatives for glucose transporter photoaffinity labeling. Carbohydr. Res.,2001,331(2),119-127.
[119]Kan, T; Kita, Y; Morohashi, Y; Tominari, Y; Hosoda, S; Tomita, T; Natsugari, H; Iwatsubo, T; Fukuyama, T.. Convenient synthesis of photoaffinity probes and evaluation of their labeling abilities. Org. Lett.,2007,9(11),2055-2058.