催化布洛芬选择性水解抗体的含磷半抗原的设计与合成
|
摘要
布洛芬(Ibuprofen)为非甾体类解热镇痛药,其消炎、镇痛、解热作用显著,不良反应较小,在世界范围内得到广泛应用,目前已成为全球最畅销的非处方药之一。S-布洛芬的药理活性为R-布洛芬的100倍,且R-布洛芬可能有些毒副作用,故消旋布洛芬的立体拆分是目前研究的一个热点。目前,文献报道的生物法拆分2-芳基丙酸类药物的途径主要有用酶或微生物进行立体选择性水解(酯、酰胺和腈)、酯化等。
磷酸酯是公认的各种酶包括许多蛋白酶和酯酶的有效过渡态类似物抑制剂。其中,1-芳基磷酸酯乙烷是具潜在生物活性的化合物,主要作为非甾体消炎镇痛药2-芳基丙酸类的类似物,如布洛芬。现已经证实1-芳基磷酸酯乙烷经过动物免疫得到的抗体具备催化立体选择性水解的功能。
本论文中,描述了一类新的生物催化剂,既抗体酶也叫催化抗体,是具有催化活性的免疫球蛋白。此类催化抗体能有效的水解外消旋布洛芬甲酯分离得到S-布洛芬。我们以抗体酶的设计策略中的过渡态理论为基础,模拟酯水解的四面体中间过渡态结构,以磷原子为四面体过渡态类似物的中心原子来设计和合成了不同的半抗原和全抗原。用目标抗原作为免疫原,经小鼠免疫单克隆抗体,然后测定抗体在水介质中与反胶束体系中的催化布洛芬甲酯选择性水解的活性。
Ibuprofen, (R,S)-2-(4-isobutylphenyl) propionic acid, is a widely used nonsteroidal anti-inflammatory drug which belongs to the family of 2-arylpropionic acid derivatives. The pharmaceutical activity of 2-arylpropionic acid derivatives is often dramatically dependent on the chirality of these compounds. In the case of ibuprofen, because of the asymmetric carbon in the second position, the S-(+)-enantiomer is known to be about 100 times more active than its R-(-)-enantiomer. Chemical synthesis of the S-isomer involving diastereomeric crystallization from a racemic acid mixture has been reported. Considerable efforts have been made in improving the methods of its asymmetric synthesis. A resolution of racemic ibuprofen has been achieved by enzyme-catalyzed or microbe cells enantioselective hydrolysis of the corresponding racemic esters, amides and nitriles.
Phosphonates are recognized as effective transition-state analogue inhibitors for a variety of enzymes including a number of proteases and esterase. Therein, 1-arylethylphosphonates are of interest as potential biologically active compounds, primarily as phosphorus analogs of 2-arylpropionic acids that are known as nonsteroid antiphlogistic and analgetic drugs, such as ibuprofen. It was demonstrated that 1-arylethylphosphonates caused formation in animal organism of antibodies possessing properties of catalysts of stereospecific hydrolysis.
In this paper, we describe a new biocatalyst, catalytic antibodies, that produced ibuprofen from their corresponding racemic ester in enantiomerically pure (S)-configuration. The biocatalyzed hydrolysis reaction can be carried out with antibodies to achieve high enantioselectivity. To elicit catalytic antibodies for the ibuprofen methyl ester hydrolysis, the tetrahedron structure compound contained phosphorus was designed and synthesized as hapten which is mimic of TSA, based on the transition state theory. The hapten was covalently attached to bovine serum albumin (BSA) to be used as immunogens. Catalytic antibodies were prepared from mice and sequential purification by ammonium sulfate precipitation and affinity chromatography.
Then, Kinetic analysis of the catalytic antibody-catalyzed reaction was found to be possible in a reverse micelle reaction system based on sodium bis (2-ethylhexyl) sodium sulfosuccinate (AOT) in isooctane. Kinetic studies showed that hydrolysis in the microemulsion system follows Michaelis-Menten kinetics.
磷酸酯是公认的各种酶包括许多蛋白酶和酯酶的有效过渡态类似物抑制剂。其中,1-芳基磷酸酯乙烷是具潜在生物活性的化合物,主要作为非甾体消炎镇痛药2-芳基丙酸类的类似物,如布洛芬。现已经证实1-芳基磷酸酯乙烷经过动物免疫得到的抗体具备催化立体选择性水解的功能。
本论文中,描述了一类新的生物催化剂,既抗体酶也叫催化抗体,是具有催化活性的免疫球蛋白。此类催化抗体能有效的水解外消旋布洛芬甲酯分离得到S-布洛芬。我们以抗体酶的设计策略中的过渡态理论为基础,模拟酯水解的四面体中间过渡态结构,以磷原子为四面体过渡态类似物的中心原子来设计和合成了不同的半抗原和全抗原。用目标抗原作为免疫原,经小鼠免疫单克隆抗体,然后测定抗体在水介质中与反胶束体系中的催化布洛芬甲酯选择性水解的活性。
Ibuprofen, (R,S)-2-(4-isobutylphenyl) propionic acid, is a widely used nonsteroidal anti-inflammatory drug which belongs to the family of 2-arylpropionic acid derivatives. The pharmaceutical activity of 2-arylpropionic acid derivatives is often dramatically dependent on the chirality of these compounds. In the case of ibuprofen, because of the asymmetric carbon in the second position, the S-(+)-enantiomer is known to be about 100 times more active than its R-(-)-enantiomer. Chemical synthesis of the S-isomer involving diastereomeric crystallization from a racemic acid mixture has been reported. Considerable efforts have been made in improving the methods of its asymmetric synthesis. A resolution of racemic ibuprofen has been achieved by enzyme-catalyzed or microbe cells enantioselective hydrolysis of the corresponding racemic esters, amides and nitriles.
Phosphonates are recognized as effective transition-state analogue inhibitors for a variety of enzymes including a number of proteases and esterase. Therein, 1-arylethylphosphonates are of interest as potential biologically active compounds, primarily as phosphorus analogs of 2-arylpropionic acids that are known as nonsteroid antiphlogistic and analgetic drugs, such as ibuprofen. It was demonstrated that 1-arylethylphosphonates caused formation in animal organism of antibodies possessing properties of catalysts of stereospecific hydrolysis.
In this paper, we describe a new biocatalyst, catalytic antibodies, that produced ibuprofen from their corresponding racemic ester in enantiomerically pure (S)-configuration. The biocatalyzed hydrolysis reaction can be carried out with antibodies to achieve high enantioselectivity. To elicit catalytic antibodies for the ibuprofen methyl ester hydrolysis, the tetrahedron structure compound contained phosphorus was designed and synthesized as hapten which is mimic of TSA, based on the transition state theory. The hapten was covalently attached to bovine serum albumin (BSA) to be used as immunogens. Catalytic antibodies were prepared from mice and sequential purification by ammonium sulfate precipitation and affinity chromatography.
Then, Kinetic analysis of the catalytic antibody-catalyzed reaction was found to be possible in a reverse micelle reaction system based on sodium bis (2-ethylhexyl) sodium sulfosuccinate (AOT) in isooctane. Kinetic studies showed that hydrolysis in the microemulsion system follows Michaelis-Menten kinetics.
引文
1.Hedstr(?)m G,Backlund M,Peter Slotte J.Enantioselective synthesis of ibuprofen esters in AOT/isooctane microemulsions by Candida cylindracea lipase[J].Biotechnol Bioengineer,1993,42(5),618.
2.Cashman,J.N.非甾体抗炎药的镇痛机理[J].国外医学.药学分册,1997,24(5),294.
3.Singer F,Maythofer F,Klein G,et al.Evaluation of the efficacy and dose - response relationship of ibuprofen(S(+) -ibuprofen) in patients with osteoarthritis of the hip and comparison with racemic ibuprofen using the WO/MAC osteo arthritis index[J].Int J Clin Pharmacol Ther.,2000,38(1),15.
4.郝秀荣,布洛芬的临床应用[J].社区医学杂志,2008,22(6),16.
5.肖畴阡,宋光泉.有机化学[M].广州:中山大学出版社,1996,pp196.
6.尹国,刘振华,曾姗姗,等;手性异构体拆分方法的研究进展[J].中国药物化学杂志,2001,11(1),57.
7.Piccolo,O.,Spreafico,F.,Visentin,G.Zinc salt catalyzed rearrangement of acetals of optically active aryl 1-chloroethyl ketones:synthesis of optically active 2-arylpropionic acids and esters[J].J.Org.Chem.1989,52,10.
8.Richards,A.Meeting the chirality challenge for the pharmaceutical industry[J].Chemica Oggi.1992,10(10),15-18
9.Lansen,R.D.,Corley,E.G.,Davis,P.2-Hydroxy esters as chiral reagents:asymmetric synthesis of 2-arylpronionic acids[J].J.Am.Chem.Soc.1989,117,7650.
10.Calmes,M.,Daunis,J.,Jacquier,R.Asymmetric synthesis of ketoprofen:a surprising base catalyst effect during asymmetric addition of pantolactone to methyl(3 -benzoylphenyl)ketene[J].Tetrahedron,1994,50,6875.
11.Thanikavelu,P.,Alicia,A.Resolution of ketoprofen[P].PCT Int.Appl.WO 9406747A 1,1994.
12.Hiroyuki,N.,Shigeya,S.,Masafumi,M.Process for optically resolving 2-(3-benzoylphenyl)propionic acid[P].Eur.Pat.Appl.EPT03212A1,1996.
13.Hamon,D.P.,Massy-Westropp,A.,Newton,J.L.Asymmetric synthesis of ibuprofen and ketoprofen[J].Tetrahedron:Asymmetr,1993,4,1435.
14.Georg,S.Crystallization process for the preparation of enantiomerically pure(S)- ketoprofen or(R)-ketoprofen[P].Ger.Offen.DE 4308865A1,1994.
15.彭立凤,赵汝淇.脂肪酶在催化合成光学活性药物中的应用[J].国外医药抗生素分册,1999,20(4),160.
16.Sih,C.J.Process for preparation(S)-2-arylpropionic acids[P].European Patent Application,EP-0227078,1987.
17.Margolin,A.L.Enzymes in the synthesis of chiral drugs[J].Enzyme Microb.Technol.1993,15,266.
18.Lalonde,J.,Govardhan,C.,Khalaf,N.Crosslinking crystals of Candida rugosa lipase:highly efficient catalysts for the resolution of chiral esters[J].J.Am.Chem.Soc.1995,117,6845.
19.Evans,C.J.,Wisdom,R.A.,Stabler,P.J.Arylalkanoic acid resolution with microorganisms [P].PCT Int.Appl.WO 9304189A1,1993.
20.Colton,I.J.,Ahmed,S.N.,Kazlauskas,R.J.A 2-propanol treatment increase the enantioselectivity of Candida rugosa lipase toward esters of chiral carboxylic acids[J].J.Org.Chem.1995,60,212.
21.Heefner,D.L.,Zepp,C.M.Enantioselective hydrolysis of ketoprofen esters by Beauveria bassiana and enzymes derived therefrom[P].PCT Int.Appl.WO 9420635A1,1994.
22.徐诗伟,徐清.酶法拆分睛类制备光学活性2-芳基丙酸[J].微生物学通报,1995,22(3),184.
23.Rossl,R.F.Enantioselective production of chiral carboxylic acids[P].US Patent 5,273,895,1993.
24.Tsai,S.W.,Wei,H.J.Enantioselectivity esterification of racemic Naproxen by lipase in organic solvent[J].Enzyme Microb.Technol.1994,16,328.
25.Lopez-Belmonte,M.T.,Alcantara,A.R.,Sinnisterra,J.V.Enantioselective esterification of 2-arylpropionic acids catalyzed by immobilized Rhizomucor miehei lipase[J].J Org Chem.1997,62,1831.
26.Mustranta,A.Use of lipases in the resolution of racemic ibuprofen.[J].Appt.Microhiol.Biotechnol.1992,38,61.
27.Tsai,S.W.,Wei,H.J.Effect of solvent on enantioselective esterification of Naproxen by lipase with trimethylsilyl methanol[J].Biotechnol.Bioeng.1994,43,64.
28.Lerner,R.A.,Tramontano,A.,Janda,K.D.,et al.Catalytic antibodies[J].Science.1986,234,1566-1570.
29.Schultz,P.G.,Pollack,S.J.,Jacobs,J.W.,et al.Selective chemical catalysis by an antibody [J].Science,1986,234,1570-1573
30.Thomas,N.R.Catalytic Antibodies and Other Biomimetic Catalysts[J].Nat.Prod.Rep.1996,13,479.
31.Blackburn,G.M.,Datta,A.,Denham,H.,et al.Catalytic antibodies[J].Adv,Phys,Org.Chem.1998,31,249.
32.Reymond,J.L.Catalytic antibodies for organic synthesis[J].Top.Curr.Chem.1999,200,59-93.
33.Hilvert,D.Stereoselective Reactions with Catalytic Antibodies[J].Top.Stereochem.1999,22,83-135.
34.Hasserodt,J.Organic Synthesis Supported by Antibody Catalysis[J].synlett.1999,12,2007-2022.
35.Salfeld,J.G.Isotype selection in antibody engineering[J].Nature Biotechnology.2007,25(12),1369-1372.
36.Smithrud,D.B.,Benkovic,P.A.,Benkovic,S.J.,et al.Cyclic peptide formation catalyzed by an antibody ligase[J].Proc Natl Acad Sci USA,2000,97(5),1953-1958.
37.Janice M Reichert,Viia E Valge-Archer.Development trends for monoclonal antibody cancer therapeutics[J].Nature Reviews Drug Discovery.2007,6(5),349-356.
38.Marasco,W.A.,Sui,J.The growth and potential of human antiviral monoclonal antibody therapeutics[J].Nature Biotechnology.2007,25(12),1421-1434.
39.Lian G,Ding L,Chen M,Liu Z,Zhao D,Ni J.Preparation and properties of a selenium-containing catalytic antibody as type Ⅰ deiodinase mimic[J]J Biol Chem,2001,276(30),28037-28041.
40.王欣,王继.抗体酶技术在医学上的应用[J],生命的化学,2005,25(5),396-399.
41.Wentworth PJr,McDunn J E,Wentworth A D,Takeuchi C,et al.Evidence for antibody-catalysed ozone formation in bacterial killing and inflammation[J].Science,2002,298(5601),2195-2199.
42.Lacroix- Desmazes S.,Bayry J.,Kavri V.S.,et al.Hayon-Sonsino D.,High levels of catalytic antibodies correlate with favorable outcome in sepsis[J].Proc Natl Acad Sci,2005,102(11),4109-4113.
43.Tanaka,F.Catalytic Antibodies as Designer Proteases and Esterases[J].Chem.Rev.2002,102,4885.
44.Gao C.S.,Lavey B.J.,Lo C.H.L.,et al.Direct selection for catalysis from combinatorial antibody libraries using a boronic acid probe:Primary.amide bond hydrolysis[J].J.Am.Chem.Soc.,1998,120,2211-2217.
45.Janda K.D.,Schloeder D.,Benkovic S.J.,et al.Induction of an antibody that catalyzes the hydrolysis of an amide bond[J].Science,1988,241,1188-1191.
46.Stewart J.D.,Krebs J.F.,Siuzdak G.,Berdis A.J.,Smithrud D.B.,Benkovic S.Dissection of an antibody-catalyzed reaction[J].Proc.Natl.Acad.Sci.U.S.A.,1994,91(16),7404-7409.
47.Thayer M.M.,Olender E.H.,Arvai A.S.,et al.Structural basis for amide hydrolysis catalyzed by the 43C9 antibody[J].J.Mol.Biol.,1999,291(2),329-345.
48.Benedetti,F.,Berti,F.,Colombatti,A.,et al.anti-Sulfonamide Antibodies Catalyse the Hydrolysis of a Heterocyclic Amide[J].Chem.Commun.1996,1417-1418.
49.Aggarwal,R.,Benedetti,F.,Berti,F.,et al.An Unprecedented Catalytic Motif Revealed in the Model Structure of Amide Hydrolyzing Antibody 312D6[J].Chem.Eur.J.2003,9,3132-3142.
50.Shah,D.O.,Lai,K.,Gorenstein,D.G.Carbon-13 NMR spectroscopy of "transition-state analog" complexes of N-acetyl-L-phenylalaninal and alpha.-chymotrypsin[J].J.Am.Chem.Soc.1984,106(15),4272-4273.
51. Thompson, R. C., Bauer, C.-A. Use of peptide aldehydes to generate transition-state analogs of elastase [J]. Biochemistry, 1979, 18, 1552-1558.
52. Martin, M. T., Angeles, T. S., Sugasawara, R., et al. Antibody-catalyzed hydrolysis of an unsubstituted amide [J]. J. Am. Chem. Soc. 1994, 116, 6508-6512.
53. Gao, C., Lavey, B. J., Lo, C.-H. L., et al. Direct selection for catalysis from combinatorial antibody libraries using a boronic acid probe: Primary amide bond hydrolysis [J]. J. Am.Chem. Soc. 1998, 120,2211.
54. Powers, J. C., Harper, J. W. In Proteinase Inhibitors; Barrett,A. J., Salvesen, G.,Eds.;Elsevier: New York, 1986; pp 3-9.
55. Wentworth, P., Jr., Datta, A., Smith, S., et al. Antibody Catalysis of BAc2 Aryl Carbamate Ester Hydrolysis: A Highly Disfavored Chemical Process [J]. J. Am. Chem. Soc. 1997, 119,2315-2316.
56. Dinaut, A. N., Chen, M.-J., Marks, A., et al. Hydrolysis of an. N-methylcarbamate by a catalytic antibody[J]. Chem. Commun. 2000, 65, 385.
57. Van Vranken, D. L., Panomitros, D., Schultz, P. G. Catalysis of Carbamate Hydrolysis by an Antibody [J]. Tetrahedron Lett. 1994, 35, 3873-3876.
58. Ikeda, S., Weinhouse, M. I., Jalda, K. D., Lerner, R. A. Asymmetric Induction via a Catalytic Antibody [J]. J. Am. Chem. Soc. 1991, 113, 7763
59. Janda, K. D., Benkovic, S. J., Lerner, R. A. Catalytic antibodies with lipase activity and R or S substrate selectivity [J]. Science 1989, 244, 437-440.
60. Pollack, S. J., Hsiun, P., Schultz, P. G. Stereospecific hydrolysis of alkyl esters by antibodies [J].J. Am. Chem. Soc. 1989,111, 5961.
61. Guo, J., Huang, W., Scanlan, T. S. In Vitro Evolution of Antibodies with Peptidase Activity [J]. J. Am. Chem. Soc. 1994, 116, 6062-6069.
62. Zhou, G. W., Guo, J., Huang, W., et al. Crystal structure of a catalytic antibody with a serine protease active site [J]. Science 1994, 265, 1059-1064.
63. Buchbinder, J. L., Stephanson, R. C., Scanlan, T. S. A comparison of the crystallographic structures of two catalytic antibodies with esterase activity [J]. J. Mol. Biol. 1998, 282,1033-1041.
64. Koren, Eugen; Smith, Holly W.; Shores, Elizabeth. Recommendations on risk-based strategies for detection and characterization of antibodies against biotechnology products [J].Journal of Immunological Methods. 2008, 333(1-2), 1-9.
65. Wade, H., Scanlan, T. S. P1-S1 interactions control the enantioselectivity and hydrolytic activity of the norleucine phenylesterase catalytic antibody 17E8 [J]. J. Am. Chem. Soc. 1996,118,6510.
66. Wade, H., Scanlan, T. S. Expression of binding energy on an antibody reaction coordinate [J].J. Am. Chem. Soc. 1999, 121, 1434, 11935-11941.
67. Fox, T., Scanlan, T. S., Kollman, P. A. Ligand Binding in the Catalytic Antibody 17E8. A Free Energy Perturbation Calcula-tion Study [J]. J. Am. Chem. Soc.1997, 119, 11571-11577.
68. Jorgenson, W. L., Chandrasekhar, J., Madhura, J. D. Comparison of Simple Potential Functions for Simulating Liquid Water [J]. J. Chem. Phys. 1983, 79, 926-935.
69. Fujii, I., Lerner, R. A., Janda, K. D. Enantiofacial protonation by catalytic antibodies [J]. J.Am. Chem. Soc. 1991,113, 8529-8538.
70. Janda, K.D., Weinhouse, M. I., Schloeder, D. M., et al. Bait and switch strategy for obtaining catalytic antibodies with acyl-transfer capabilities [J]. J. Am. Soc, 1990, 112 (3), 1274.
71. Janda, K. D., Weinhouse, M. I., Danon, T., et al. Asymmetric induction via a catalytic antibody [J]. J. Am. Chem. Soc. 1991, 113, 5427-5434.
72. Suga, H., Ersoy, O., Tsumuraya, T., et al. Esterolytic antibodies induced to haptens with a 1,2-amino alcohol functionality [J]. J. Am. Chem. Soc. 1994, 116, 487-494.
73. Florez-Alvarez, J., Brocklehurst, K., Gallacher, G. Synthesis of an aminoalcohol hapten for the generation of catalytic antibodies [J]. Tetrahedron Lett. 2002, 43, 171-174.
74. Tsumuraya, T., Takazawa, N., Tsunakawa, A., et al. Catalytic antibodies induced by a zwitterionic hapten [J]. Chem. sEur. J. 2001, 7, 3748-3755.
75. Iwabuchi, Y., Kurihara, S., Oda, M. Synthesis of chiral, densely functionalized medium-sized rings from carbohydrate precursors via regioselective exo/endo-pvimary alkyl radical cyclizations [J]. Tetrahedron Lett. 1999,40, 5341-5345.
76. Grynszpan, F., Keinan, E. Use of antibodies to dissect the components of a catalytic event: The cyclopropenone hapten [J]. Chem. Commun. 1998, 865.
77. Patten PA., et al. The immunological evolution of catalysis [J]. Science, 1996, 271,1086-1091
78.Guo J,Huang W,Zhou GW,Fletterick RJ and Scanlon TS.Mechanistically different catalytic antibodies obtained from immunization with a single transition-state analog[J].Proc Natl Acad Sci USA,1995,92,1694-1698.
79.Campbel D.A.,Gong B.,Kocheresperger L.M.,et al.An Antibody Activated Prodrug[J].J.Am.Chem.Soc.,1994,116,2165.
80.Tsumuraya T.et al.Catalytic Antibodies Generated via Homologous and Heterologous Immunization[J].J.Am.Chem.Soc.,1995,117,11390-11396
81.Wirshing,P.,Ashley,J.A.,Lo,C.-H.L.,et al.Reactive Immunization[J].Science 1995,270,1775-1783.
82.Wagner,J.,Lerner,R.A.,Barbas,C.F.,Ⅲ.Efficient aldolase catalytic antibodies that use the enamine mechanism of natural enzymes[J].Science 1995,270,1797-1800.
83.Tanaka,.F.,Almer,H.,Lerner,R.A.,Barbas,C.F.,Ⅲ.Catalytic single-chain antibodies possessing β-lactamase activity selected from a phage displayed combinatorial library using a mechanism-based inhibitor[J].Tetrahedron Lett.1999,40,8063-8066.
84.Janda,K.D.,Lo,C.-H.L.,Li,T.,et al.Direct selection for a catalytic mechanism from combinatorial antibody libraries[J].Proc.Natl.Acad.Sci.U.S.A.1994,91,2532.
85.张伦.萘普生市场透析[J].中国制药信息,2002,18(8),32.
86.Evans A.M.Enantioselective pharmacodynamics and pharmacokinetics of chiral non-steroidal anti-inflammatory drugs[J].Eur.J.Chin.Pharmacol.1992,42(3),237-256.
87.Larsen,N.A.,et al.Crystallographic and biochemical analysis of cocaine-degrading antibody 15A10[J].Biochemistry,2004,43(25):8067-8076.
88.李述文,范加霖.实用有机化学手册[M].上海:上海科学技术出版社,1981,257-259
89.胡允金.中国科学院上海有机化学研究所博士论文,1997
90.杨利国,胡少旭,魏平华,等.酶免疫检测技术[M].南京:南京大学出版社,1998,pp242-476.
91.Zhang Y et al.Molecular simulation studies of a selenium-containing scFv catalytic antibo[J].Biochim Biophys Acta,2005,1747(1),27-34
92.Bradford M M.A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding[J].Anal Biochem.1976,72,248-254
93.Li C-P,Shi Q-H,Li L,et al.High performance liquid chromatographic separation of ibuprofen enantiomer with chiral mobile phase additives[J].Chin J Pharm Anal,2005,25(4),426-428
94.Kotlarchyk M,Chen S H,Huang J S,et al.Structure of three-component microemulsions in the critical region determined by small-angle neutron scattering[J].Phys Rev A,1984,29,2054-2069
95.Gutyukinal,N.S.Synthesis of Biologically Active 1-Arylemylphosphonates[J].Russian Journal of Organic Chemistry,2002,4(38),573-587
96.Michael D.Synthsis of alkyl- and arylphosphonic acid monoesters by direct esterification of dibasic phosphonic acids in the presence of an arsenic acid catalyst[J].Phoshporus Sulfur and,Silicon,2004,179,1509-1516
97.Li-Biao Han and Masato Tanaka~*.Palladium-Catalyzed Hvdrophosphorvlation of Alkynes via Oxidative Addition of HP(O)(OR)_2[J].J.Am.Soc.1996,118,1571-1572
98.樊能廷.有机合成事典[M].北京:北京理工大学出版社,1992,222-223
2.Cashman,J.N.非甾体抗炎药的镇痛机理[J].国外医学.药学分册,1997,24(5),294.
3.Singer F,Maythofer F,Klein G,et al.Evaluation of the efficacy and dose - response relationship of ibuprofen(S(+) -ibuprofen) in patients with osteoarthritis of the hip and comparison with racemic ibuprofen using the WO/MAC osteo arthritis index[J].Int J Clin Pharmacol Ther.,2000,38(1),15.
4.郝秀荣,布洛芬的临床应用[J].社区医学杂志,2008,22(6),16.
5.肖畴阡,宋光泉.有机化学[M].广州:中山大学出版社,1996,pp196.
6.尹国,刘振华,曾姗姗,等;手性异构体拆分方法的研究进展[J].中国药物化学杂志,2001,11(1),57.
7.Piccolo,O.,Spreafico,F.,Visentin,G.Zinc salt catalyzed rearrangement of acetals of optically active aryl 1-chloroethyl ketones:synthesis of optically active 2-arylpropionic acids and esters[J].J.Org.Chem.1989,52,10.
8.Richards,A.Meeting the chirality challenge for the pharmaceutical industry[J].Chemica Oggi.1992,10(10),15-18
9.Lansen,R.D.,Corley,E.G.,Davis,P.2-Hydroxy esters as chiral reagents:asymmetric synthesis of 2-arylpronionic acids[J].J.Am.Chem.Soc.1989,117,7650.
10.Calmes,M.,Daunis,J.,Jacquier,R.Asymmetric synthesis of ketoprofen:a surprising base catalyst effect during asymmetric addition of pantolactone to methyl(3 -benzoylphenyl)ketene[J].Tetrahedron,1994,50,6875.
11.Thanikavelu,P.,Alicia,A.Resolution of ketoprofen[P].PCT Int.Appl.WO 9406747A 1,1994.
12.Hiroyuki,N.,Shigeya,S.,Masafumi,M.Process for optically resolving 2-(3-benzoylphenyl)propionic acid[P].Eur.Pat.Appl.EPT03212A1,1996.
13.Hamon,D.P.,Massy-Westropp,A.,Newton,J.L.Asymmetric synthesis of ibuprofen and ketoprofen[J].Tetrahedron:Asymmetr,1993,4,1435.
14.Georg,S.Crystallization process for the preparation of enantiomerically pure(S)- ketoprofen or(R)-ketoprofen[P].Ger.Offen.DE 4308865A1,1994.
15.彭立凤,赵汝淇.脂肪酶在催化合成光学活性药物中的应用[J].国外医药抗生素分册,1999,20(4),160.
16.Sih,C.J.Process for preparation(S)-2-arylpropionic acids[P].European Patent Application,EP-0227078,1987.
17.Margolin,A.L.Enzymes in the synthesis of chiral drugs[J].Enzyme Microb.Technol.1993,15,266.
18.Lalonde,J.,Govardhan,C.,Khalaf,N.Crosslinking crystals of Candida rugosa lipase:highly efficient catalysts for the resolution of chiral esters[J].J.Am.Chem.Soc.1995,117,6845.
19.Evans,C.J.,Wisdom,R.A.,Stabler,P.J.Arylalkanoic acid resolution with microorganisms [P].PCT Int.Appl.WO 9304189A1,1993.
20.Colton,I.J.,Ahmed,S.N.,Kazlauskas,R.J.A 2-propanol treatment increase the enantioselectivity of Candida rugosa lipase toward esters of chiral carboxylic acids[J].J.Org.Chem.1995,60,212.
21.Heefner,D.L.,Zepp,C.M.Enantioselective hydrolysis of ketoprofen esters by Beauveria bassiana and enzymes derived therefrom[P].PCT Int.Appl.WO 9420635A1,1994.
22.徐诗伟,徐清.酶法拆分睛类制备光学活性2-芳基丙酸[J].微生物学通报,1995,22(3),184.
23.Rossl,R.F.Enantioselective production of chiral carboxylic acids[P].US Patent 5,273,895,1993.
24.Tsai,S.W.,Wei,H.J.Enantioselectivity esterification of racemic Naproxen by lipase in organic solvent[J].Enzyme Microb.Technol.1994,16,328.
25.Lopez-Belmonte,M.T.,Alcantara,A.R.,Sinnisterra,J.V.Enantioselective esterification of 2-arylpropionic acids catalyzed by immobilized Rhizomucor miehei lipase[J].J Org Chem.1997,62,1831.
26.Mustranta,A.Use of lipases in the resolution of racemic ibuprofen.[J].Appt.Microhiol.Biotechnol.1992,38,61.
27.Tsai,S.W.,Wei,H.J.Effect of solvent on enantioselective esterification of Naproxen by lipase with trimethylsilyl methanol[J].Biotechnol.Bioeng.1994,43,64.
28.Lerner,R.A.,Tramontano,A.,Janda,K.D.,et al.Catalytic antibodies[J].Science.1986,234,1566-1570.
29.Schultz,P.G.,Pollack,S.J.,Jacobs,J.W.,et al.Selective chemical catalysis by an antibody [J].Science,1986,234,1570-1573
30.Thomas,N.R.Catalytic Antibodies and Other Biomimetic Catalysts[J].Nat.Prod.Rep.1996,13,479.
31.Blackburn,G.M.,Datta,A.,Denham,H.,et al.Catalytic antibodies[J].Adv,Phys,Org.Chem.1998,31,249.
32.Reymond,J.L.Catalytic antibodies for organic synthesis[J].Top.Curr.Chem.1999,200,59-93.
33.Hilvert,D.Stereoselective Reactions with Catalytic Antibodies[J].Top.Stereochem.1999,22,83-135.
34.Hasserodt,J.Organic Synthesis Supported by Antibody Catalysis[J].synlett.1999,12,2007-2022.
35.Salfeld,J.G.Isotype selection in antibody engineering[J].Nature Biotechnology.2007,25(12),1369-1372.
36.Smithrud,D.B.,Benkovic,P.A.,Benkovic,S.J.,et al.Cyclic peptide formation catalyzed by an antibody ligase[J].Proc Natl Acad Sci USA,2000,97(5),1953-1958.
37.Janice M Reichert,Viia E Valge-Archer.Development trends for monoclonal antibody cancer therapeutics[J].Nature Reviews Drug Discovery.2007,6(5),349-356.
38.Marasco,W.A.,Sui,J.The growth and potential of human antiviral monoclonal antibody therapeutics[J].Nature Biotechnology.2007,25(12),1421-1434.
39.Lian G,Ding L,Chen M,Liu Z,Zhao D,Ni J.Preparation and properties of a selenium-containing catalytic antibody as type Ⅰ deiodinase mimic[J]J Biol Chem,2001,276(30),28037-28041.
40.王欣,王继.抗体酶技术在医学上的应用[J],生命的化学,2005,25(5),396-399.
41.Wentworth PJr,McDunn J E,Wentworth A D,Takeuchi C,et al.Evidence for antibody-catalysed ozone formation in bacterial killing and inflammation[J].Science,2002,298(5601),2195-2199.
42.Lacroix- Desmazes S.,Bayry J.,Kavri V.S.,et al.Hayon-Sonsino D.,High levels of catalytic antibodies correlate with favorable outcome in sepsis[J].Proc Natl Acad Sci,2005,102(11),4109-4113.
43.Tanaka,F.Catalytic Antibodies as Designer Proteases and Esterases[J].Chem.Rev.2002,102,4885.
44.Gao C.S.,Lavey B.J.,Lo C.H.L.,et al.Direct selection for catalysis from combinatorial antibody libraries using a boronic acid probe:Primary.amide bond hydrolysis[J].J.Am.Chem.Soc.,1998,120,2211-2217.
45.Janda K.D.,Schloeder D.,Benkovic S.J.,et al.Induction of an antibody that catalyzes the hydrolysis of an amide bond[J].Science,1988,241,1188-1191.
46.Stewart J.D.,Krebs J.F.,Siuzdak G.,Berdis A.J.,Smithrud D.B.,Benkovic S.Dissection of an antibody-catalyzed reaction[J].Proc.Natl.Acad.Sci.U.S.A.,1994,91(16),7404-7409.
47.Thayer M.M.,Olender E.H.,Arvai A.S.,et al.Structural basis for amide hydrolysis catalyzed by the 43C9 antibody[J].J.Mol.Biol.,1999,291(2),329-345.
48.Benedetti,F.,Berti,F.,Colombatti,A.,et al.anti-Sulfonamide Antibodies Catalyse the Hydrolysis of a Heterocyclic Amide[J].Chem.Commun.1996,1417-1418.
49.Aggarwal,R.,Benedetti,F.,Berti,F.,et al.An Unprecedented Catalytic Motif Revealed in the Model Structure of Amide Hydrolyzing Antibody 312D6[J].Chem.Eur.J.2003,9,3132-3142.
50.Shah,D.O.,Lai,K.,Gorenstein,D.G.Carbon-13 NMR spectroscopy of "transition-state analog" complexes of N-acetyl-L-phenylalaninal and alpha.-chymotrypsin[J].J.Am.Chem.Soc.1984,106(15),4272-4273.
51. Thompson, R. C., Bauer, C.-A. Use of peptide aldehydes to generate transition-state analogs of elastase [J]. Biochemistry, 1979, 18, 1552-1558.
52. Martin, M. T., Angeles, T. S., Sugasawara, R., et al. Antibody-catalyzed hydrolysis of an unsubstituted amide [J]. J. Am. Chem. Soc. 1994, 116, 6508-6512.
53. Gao, C., Lavey, B. J., Lo, C.-H. L., et al. Direct selection for catalysis from combinatorial antibody libraries using a boronic acid probe: Primary amide bond hydrolysis [J]. J. Am.Chem. Soc. 1998, 120,2211.
54. Powers, J. C., Harper, J. W. In Proteinase Inhibitors; Barrett,A. J., Salvesen, G.,Eds.;Elsevier: New York, 1986; pp 3-9.
55. Wentworth, P., Jr., Datta, A., Smith, S., et al. Antibody Catalysis of BAc2 Aryl Carbamate Ester Hydrolysis: A Highly Disfavored Chemical Process [J]. J. Am. Chem. Soc. 1997, 119,2315-2316.
56. Dinaut, A. N., Chen, M.-J., Marks, A., et al. Hydrolysis of an. N-methylcarbamate by a catalytic antibody[J]. Chem. Commun. 2000, 65, 385.
57. Van Vranken, D. L., Panomitros, D., Schultz, P. G. Catalysis of Carbamate Hydrolysis by an Antibody [J]. Tetrahedron Lett. 1994, 35, 3873-3876.
58. Ikeda, S., Weinhouse, M. I., Jalda, K. D., Lerner, R. A. Asymmetric Induction via a Catalytic Antibody [J]. J. Am. Chem. Soc. 1991, 113, 7763
59. Janda, K. D., Benkovic, S. J., Lerner, R. A. Catalytic antibodies with lipase activity and R or S substrate selectivity [J]. Science 1989, 244, 437-440.
60. Pollack, S. J., Hsiun, P., Schultz, P. G. Stereospecific hydrolysis of alkyl esters by antibodies [J].J. Am. Chem. Soc. 1989,111, 5961.
61. Guo, J., Huang, W., Scanlan, T. S. In Vitro Evolution of Antibodies with Peptidase Activity [J]. J. Am. Chem. Soc. 1994, 116, 6062-6069.
62. Zhou, G. W., Guo, J., Huang, W., et al. Crystal structure of a catalytic antibody with a serine protease active site [J]. Science 1994, 265, 1059-1064.
63. Buchbinder, J. L., Stephanson, R. C., Scanlan, T. S. A comparison of the crystallographic structures of two catalytic antibodies with esterase activity [J]. J. Mol. Biol. 1998, 282,1033-1041.
64. Koren, Eugen; Smith, Holly W.; Shores, Elizabeth. Recommendations on risk-based strategies for detection and characterization of antibodies against biotechnology products [J].Journal of Immunological Methods. 2008, 333(1-2), 1-9.
65. Wade, H., Scanlan, T. S. P1-S1 interactions control the enantioselectivity and hydrolytic activity of the norleucine phenylesterase catalytic antibody 17E8 [J]. J. Am. Chem. Soc. 1996,118,6510.
66. Wade, H., Scanlan, T. S. Expression of binding energy on an antibody reaction coordinate [J].J. Am. Chem. Soc. 1999, 121, 1434, 11935-11941.
67. Fox, T., Scanlan, T. S., Kollman, P. A. Ligand Binding in the Catalytic Antibody 17E8. A Free Energy Perturbation Calcula-tion Study [J]. J. Am. Chem. Soc.1997, 119, 11571-11577.
68. Jorgenson, W. L., Chandrasekhar, J., Madhura, J. D. Comparison of Simple Potential Functions for Simulating Liquid Water [J]. J. Chem. Phys. 1983, 79, 926-935.
69. Fujii, I., Lerner, R. A., Janda, K. D. Enantiofacial protonation by catalytic antibodies [J]. J.Am. Chem. Soc. 1991,113, 8529-8538.
70. Janda, K.D., Weinhouse, M. I., Schloeder, D. M., et al. Bait and switch strategy for obtaining catalytic antibodies with acyl-transfer capabilities [J]. J. Am. Soc, 1990, 112 (3), 1274.
71. Janda, K. D., Weinhouse, M. I., Danon, T., et al. Asymmetric induction via a catalytic antibody [J]. J. Am. Chem. Soc. 1991, 113, 5427-5434.
72. Suga, H., Ersoy, O., Tsumuraya, T., et al. Esterolytic antibodies induced to haptens with a 1,2-amino alcohol functionality [J]. J. Am. Chem. Soc. 1994, 116, 487-494.
73. Florez-Alvarez, J., Brocklehurst, K., Gallacher, G. Synthesis of an aminoalcohol hapten for the generation of catalytic antibodies [J]. Tetrahedron Lett. 2002, 43, 171-174.
74. Tsumuraya, T., Takazawa, N., Tsunakawa, A., et al. Catalytic antibodies induced by a zwitterionic hapten [J]. Chem. sEur. J. 2001, 7, 3748-3755.
75. Iwabuchi, Y., Kurihara, S., Oda, M. Synthesis of chiral, densely functionalized medium-sized rings from carbohydrate precursors via regioselective exo/endo-pvimary alkyl radical cyclizations [J]. Tetrahedron Lett. 1999,40, 5341-5345.
76. Grynszpan, F., Keinan, E. Use of antibodies to dissect the components of a catalytic event: The cyclopropenone hapten [J]. Chem. Commun. 1998, 865.
77. Patten PA., et al. The immunological evolution of catalysis [J]. Science, 1996, 271,1086-1091
78.Guo J,Huang W,Zhou GW,Fletterick RJ and Scanlon TS.Mechanistically different catalytic antibodies obtained from immunization with a single transition-state analog[J].Proc Natl Acad Sci USA,1995,92,1694-1698.
79.Campbel D.A.,Gong B.,Kocheresperger L.M.,et al.An Antibody Activated Prodrug[J].J.Am.Chem.Soc.,1994,116,2165.
80.Tsumuraya T.et al.Catalytic Antibodies Generated via Homologous and Heterologous Immunization[J].J.Am.Chem.Soc.,1995,117,11390-11396
81.Wirshing,P.,Ashley,J.A.,Lo,C.-H.L.,et al.Reactive Immunization[J].Science 1995,270,1775-1783.
82.Wagner,J.,Lerner,R.A.,Barbas,C.F.,Ⅲ.Efficient aldolase catalytic antibodies that use the enamine mechanism of natural enzymes[J].Science 1995,270,1797-1800.
83.Tanaka,.F.,Almer,H.,Lerner,R.A.,Barbas,C.F.,Ⅲ.Catalytic single-chain antibodies possessing β-lactamase activity selected from a phage displayed combinatorial library using a mechanism-based inhibitor[J].Tetrahedron Lett.1999,40,8063-8066.
84.Janda,K.D.,Lo,C.-H.L.,Li,T.,et al.Direct selection for a catalytic mechanism from combinatorial antibody libraries[J].Proc.Natl.Acad.Sci.U.S.A.1994,91,2532.
85.张伦.萘普生市场透析[J].中国制药信息,2002,18(8),32.
86.Evans A.M.Enantioselective pharmacodynamics and pharmacokinetics of chiral non-steroidal anti-inflammatory drugs[J].Eur.J.Chin.Pharmacol.1992,42(3),237-256.
87.Larsen,N.A.,et al.Crystallographic and biochemical analysis of cocaine-degrading antibody 15A10[J].Biochemistry,2004,43(25):8067-8076.
88.李述文,范加霖.实用有机化学手册[M].上海:上海科学技术出版社,1981,257-259
89.胡允金.中国科学院上海有机化学研究所博士论文,1997
90.杨利国,胡少旭,魏平华,等.酶免疫检测技术[M].南京:南京大学出版社,1998,pp242-476.
91.Zhang Y et al.Molecular simulation studies of a selenium-containing scFv catalytic antibo[J].Biochim Biophys Acta,2005,1747(1),27-34
92.Bradford M M.A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding[J].Anal Biochem.1976,72,248-254
93.Li C-P,Shi Q-H,Li L,et al.High performance liquid chromatographic separation of ibuprofen enantiomer with chiral mobile phase additives[J].Chin J Pharm Anal,2005,25(4),426-428
94.Kotlarchyk M,Chen S H,Huang J S,et al.Structure of three-component microemulsions in the critical region determined by small-angle neutron scattering[J].Phys Rev A,1984,29,2054-2069
95.Gutyukinal,N.S.Synthesis of Biologically Active 1-Arylemylphosphonates[J].Russian Journal of Organic Chemistry,2002,4(38),573-587
96.Michael D.Synthsis of alkyl- and arylphosphonic acid monoesters by direct esterification of dibasic phosphonic acids in the presence of an arsenic acid catalyst[J].Phoshporus Sulfur and,Silicon,2004,179,1509-1516
97.Li-Biao Han and Masato Tanaka~*.Palladium-Catalyzed Hvdrophosphorvlation of Alkynes via Oxidative Addition of HP(O)(OR)_2[J].J.Am.Soc.1996,118,1571-1572
98.樊能廷.有机合成事典[M].北京:北京理工大学出版社,1992,222-223