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研究生(外文):Chung-Yee Shieh
論文名稱(外文):The study and synthesis of N-acetyl-leucyl-leucyl-norleucinal derivatives
指導教授(外文):Shen-Fang SuChing-Yuh Chern
外文關鍵詞:solution-phase peptide synthesisP-glycopriteinALLN derivatives
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P-glycoprotein (Pgp)是一個與抗癌藥物之多重抗藥性(multiple-drug resistance)有關的運送子。Pgp其主要作用能將藥物自細胞內排出,因而降低藥物於細胞內的蓄積。
文獻指出厭水性的peptide,如ALLN (N-acetyl-leucyl-leucyl- norleucinal)、ALLM (N-acetyl-leucyl-leucyl-methiminal)、leupeptin (N-acetyl-leucyl-leucyl-arginal)為 Pgp的受質或抑制劑。本實驗以N-acetyl- leucyl-leucine為主架構,欲合成出一系列的線性peptide,有助於未來將此系列peptide應用於與Pgp間 interaction 的研究。
本實驗選用液態peptide合成法,合成出N-acetyl- leucyl-leucine benzyl、N-acetyl- leucyl-leucine、N-acetyl- leucyl-leucyl-tryptophanol、N-acetyl- leucyl-leucyl-CBZ-lysinol、 N-acetyl- leucyl-leucyl- phenylalaninol。
P-glycoprotein (Pgp), the multidrug resistance gene (mdr1) product, reduces the intracellular accumulation of a variety of drugs by pumping drugs out of membranes.
Studies have demonstrated that hydrophobic tripeptides N-acetyl- leucyl- leucyl-norleucinal (ALLN), N-acetyl- leucyl-leucyl-methiminal (ALLM) and N-acetyl-leucyl-leucyl-arginal (leupeptin) are Pgp substrates/inhibitors. We would like to synthesize a series of tripeptides (N-acetyl-leu-leu-X ) and to study the interaction between the tripeptides and Pgp.
We employ liquid-phase peptide synthesis method to obtain. We synthesize the N-acetyl-leucyl-leucine benzyl、N-acetyl-leucyl-leucine、N-acetyl-leucyl-leucyl-tryptophanol、N-acetyl-leucyl-leucyl-CBZ-lysinol、 N-acetyl-leucyl-leucyl-phenylalaninol.
中文摘要 I
英文摘要 II
誌謝 III
目錄 IV
表目錄 V
圖目錄 VI
第壹章 緒論 1
第貳章 peptide之合成 3
第一節、peptide合成之發展 3
第二節、peptide合成法之介紹 6
第三節、peptide的純化 24
第參章 peptide合成的應用 26
第肆章 研究目的 37
第伍章 實驗材料、儀器及方法 38
第一節、材料 38
第二節、儀器 40
第三節、實驗方法 42
第陸章 結果 53
第柒章 討論 73
參考文獻 77

表1、一般peptide合成時所用的側鏈保護基 15
表2、常用於移除peptide的混合試劑 22
表3、本實驗合成所得之peptide 73

圖1、 Stepwise的peptide合成 ..9
圖2、 Merrifield的solid-phase peptide synthesis .20
圖3、 oxytocin之結構式 .26
圖4、 R121和R205的結構式 32
圖5、 Retro-synthesis 之1 42
圖6、 Retro-synthesis 之2 43
圖7、 Tryptophanol(1)1H核磁共振光譜圖 58
圖8、 Tryptophanol(1)13C核磁共振光譜圖 59
圖9、 Tryptophanol(1)Mass 60
圖10、Benzyloxycarbonly lysinol (2)1H核磁共振光譜圖 61
圖11、Benzyloxycarbonly lysinol (2)13C核磁共振光譜圖 62
圖12、Benzyloxycarbonly lysinol (2)Mass 63
圖13、N-acetyl-leucyl-leucyl benzyl (3)1H核磁共振光譜圖 64
圖14、N-acetyl-leucyl-leucyl benzyl (3)13C核磁共振光譜圖 65
圖15、N-acetyl-leucyl-leucyl benzyl (3)Mass 66
圖16、N-acetyl-leucyl-leucine (4)1H核磁共振光譜圖 67
圖17、N-acetyl-leucyl-leucine (4)13C核磁共振光譜圖 68
圖18、N-acetyl-leucyl-leucine (4)Mass 69
圖19、N-acteyl-leucyl-leucyl-phenylalaninol (5)1H核磁共振光譜圖 70
圖20、N-acteyl-leucyl-leucyl-phenylalaninol (5)13C核磁共振光譜圖 71
圖21、N-acteyl-leucyl-leucyl-phenylalaninol (5)Mass 72
圖22、ALLN (N-acteyl-leucyl-leucyl-norleucinal) 之結構式 75
圖23、未純化之tripeptide結構式 75
Arnon, R.: Synthetic peptides as the basis for vaccine design. Mol Immunol 28: 209-15., 1991
Bai, J. P.: pGlu-L-Dopa-Pro: a tripeptide prodrug targeting the intestinal peptide transporter for absorption and tissue enzymes for conversion. Pharm Res 12: 1101-4., 1995
Ball, H. L. and Mascagni, P.: Chemical synthesis and purification of proteins: a methodology. Int J Pept Protein Res 48: 31-47, 1996
Belleau, B. and Malek, G.: A new convenient reagent for peptide syntheses. J Am Chem Soc 90: 1651-2., 1968
Bilek, R., Bradbury, A. F., and Smyth, D. G.: Synthesis and high-performance liquid chromatographic purification of tritiated thyrotrophin-releasing hormone-like peptides. J Chromatogr B Biomed Appl 656: 115-8., 1994
Bittle, J. L., Houghten, R. A., Alexander, H., Shinnick, T. M., Sutcliffe, J. G., Lerner, R. A., Rowlands, D. J., and Brown, F.: Protection against foot-and-mouth disease by immunization with a chemically synthesized peptide predicted from the viral nucleotide sequence. Nature 298: 30-3., 1982
Bodanszky, M.: Synthesis of peptides by aminolysis of nitrophenyl esters. Nature (London) 175: 685, 1955
Bodanszky, M.: In search of new methods in peptide synthesis. A review of the last three decades. Int J Pept Protein Res 25: 449-74., 1985
Bodanszky, M.: Principles of peptide synthesis, New York, 1993
Borgnia, M. J., Eytan, G. D., and Assaraf, Y. G.: Competition of hydrophobic peptides, cytotoxic drugs, and chemosensitizers on a common P-glycoprotein pharmacophore as revealed by its ATPase activity. J Biol Chem 271: 3163-71, 1996
Bosze, S., Mak, M., Medzihradszky-Schweiger, H., and Hudecz, F.: Chromatographic characterization of HSV-1 gD 268-284 and IL-6 179-185 synthetic oligopeptides by reversed-phase high-performance liquid chromatography, automated Edman degradation and mass spectrometric analysis. J Chromatogr A 668: 345-51, 1994
Burton, P. S., Conradi, R. A., Hilgers, A. R., Ho, N. F. H., and Maggiora, L. L.: The relationship between peptide structure and transport across epithelial cell monolayers. J. Controlled Releae 19: 87-9, 1992
Calvo-Calle, J. M., de Oliveira, G. A., Clavijo, P., Maracic, M., Tam, J. P., Lu, Y. A., Nardin, E. H., Nussenzweig, R. S., and Cochrane, A. H.: Immunogenicity of multiple antigen peptides containing B and non-repeat T cell epitopes of the circumsporozoite protein of Plasmodium falciparum. J Immunol 150: 1403-12., 1993
Canova-Davis, E., Baldonado, I. P., and Teshima, G. M.: Characterization of chemically synthesized human relaxin by high- performance liquid chromatography. J Chromatogr 508: 81-96., 1990
Carpino, L. A.: Oxidative reactions of hydrazines. IV. elimination of nitrogen from 1,1-Disubstituted-2-arenesulfonhydrazides. J Am Chem Soc 79: 4427-31, 1957
Carpino, L. A. and Han, G. Y.: The 9-fluorenylmethoxycarbonyl function, a new base-sensitive amino-protecting group. J Am Chem Soc 92: 5748-9, 1970
Carpino, L. A. and Han, G. Y.: The 9-Fluorenylmethoxycarbonyl Amino-Protecting Group. J. Org. Chem. 37: 3044-9, 1972
Coe, D. M. and Storer, R.: Solution-phase combinatorial chemistry. Mol Divers 4: 31-8, 1998
Conradi, R. A., Hilgers, A. R., Ho, N. F., and Burton, P. S.: The influence of peptide structure on transport across Caco-2 cells. II. Peptide bond modification which results in improved permeability. Pharm Res 9: 435-9., 1992
Cornille, F., Wecker, K., Loffet, A., Genet, R., and Roques, B.: Efficient solid-phase synthesis of Vpr from HIV-1 using low quantities of uniformly 13C-, 15N-labeled amino acids for NMR structural studies. J Pept Res 54: 427-35., 1999
Curtius, T.: Ueber die einwirkung von chlorbenzoyl auf glycocollsiber. J. Pract. Chem. 24: 239-41, 1881
de Jong, M. C., Slootstra, J. W., Scheffer, G. L., Schroeijers, A. B., Puijk, W. C., Dinkelberg, R., Kool, M., Broxterman, H. J., Meloen, R. H., and Scheper, R. J.: Peptide transport by the multidrug resistance protein MRP1. Cancer Res 61: 2552-7, 2001
Dowdy, S. F., Hinds, P. W., Louie, K., Reed, S. I., Arnold, A., and Weinberg, R. A.: Physical interaction of the retinoblastoma protein with human D cyclins. Cell 73: 499-511., 1993
Dunn, B. M. and Pennington, M. W.: Peptide analysis protocols, Totowa, N. J., 1994
Fields, C. G., Fields, G. B., Noble, R. L., and Cross, T. A.: Solid phase peptide synthesis of 15N-gramicidins A, B, and C and high performance liquid chromatographic purification. Int J Pept Protein Res 33: 298-303., 1989
Fournier, A., Couvineau, A., and Laburthe, M.: Synthesis of a hydrophilic affinity matrix for the purification of the vasoactive intestinal peptide receptor. Anal Biochem 211: 305-10., 1993
Fox, J. E.: Multiple peptide synthesis. Mol Biotechnol 3: 249-58., 1995
Francis, M. J., Hastings, G. Z., Clarke, B. E., Brown, A. L., Beddell, C. R., Rowlands, D. J., and Brown, F.: Neutralizing antibodies to all seven serotypes of foot-and-mouth disease virus elicited by synthetic peptides. Immunology 69: 171-6., 1990
Fridkin, M. and Patchornik, A.: Peptide synthesis. Annu Rev Biochem 43: 419-43, 1974
Funakoshi, S., Fukuda, H., and Fujii, N.: Chemoselective one-step purification method for peptides synthesized by the solid-phase technique. Proc Natl Acad Sci U S A 88: 6981-5., 1991
Gade, G. and Hayes, T. K.: Structure-activity relationships for Periplaneta americana hypertrehalosemic hormone. I: The importance of side chains and termini. Peptides 16: 1173-80, 1995
Gairi, M., Lloyd-Williams, P., Albericio, F., and Giralt, E.: Convergent solid-phase peptide synthesis. 12. Chromatographic techniques for the purification of protected peptide segments. Int J Pept Protein Res 46: 119-33., 1995
Gao, J., Sudoh, M., Aube, J., and Borchardt, R. T.: Transport characteristics of peptides and peptidomimetics: I. N-methylated peptides as substrates for the oligopeptide transporter and P-glycoprotein in the intestinal mucosa. J Pept Res 57: 316-29, 2001
Greenbaum, L. M., Grebow, P., Johnston, M., Prakash, A., and Semente, G.: Pepstatin, an inhibitor of leukokinin formation and ascitic fluid accumulation. Cancer Res 35: 706-10., 1975
Hancock, D. C., O'Reilly, N. J., and Evan, G. I.: Synthetic peptides in biochemical research. Mol Biotechnol 4: 73-86., 1995
Jones, J.: Amino acid and peptide synthesis, New York, 1992
Kleinkauf, H. and von Dohren, H.: Applications of peptide synthetases in the synthesis of peptide analogues. Acta Biochim Pol 44: 839-47, 1997
Kochs, G., Hummel, R., Meyer, D., Hug, H., Marme, D., and Sarre, T. F.: Activation and substrate specificity of the human protein kinase C alpha and zeta isoenzymes. Eur J Biochem 216: 597-606., 1993
Kovacs, J., Kisfaludy, L., and Ceprini, M. Q.: On the optical purity of peptide active esters prepared by N,N'- dicyclohexylcarbodiimide and "complexes" of N,N'- dicyclohexylcarbodiimide-pentachlorophenol and N,N'- dicyclohexylcarbodiimide-pentafluorophenol. J Am Chem Soc 89: 183-4., 1967
Larsson, M., Lovgren, K., and Morein, B.: Immunopotentiation of synthetic oligopeptides by chemical conjugation to iscoms. J Immunol Methods 162: 257-60., 1993
Lerner, R. A., Green, N., Alexander, H., Liu, F. T., Sutcliffe, J. G., and Shinnick, T. M.: Chemically synthesized peptides predicted from the nucleotide sequence of the hepatitis B virus genome elicit antibodies reactive with the native envelope protein of Dane particles. Proc Natl Acad Sci U S A 78: 3403-7., 1981
Li, S. and Dass, C.: Iron(III)-immobilized metal ion affinity chromatography and mass spectrometry for the purification and characterization of synthetic phosphopeptides. Anal Biochem 270: 9-14., 1999
Linde, C. M., Hoffner, S. E., Refai, E., and Andersson, M.: In vitro activity of PR-39, a proline-arginine-rich peptide, against susceptible and multi-drug-resistant Mycobacterium tuberculosis. J Antimicrob Chemother 47: 575-80., 2001
Liu, S. and Heinrikson, C.: Chemical synthesis and sequencing of peptides and protein, 1981
McKay, F. C. and Albertson, N. F.: New amine-masking groups for peptide synthesis. J Am Chem Soc 79: 4686-90, 1957
Merrifield, B.: Concept and early development of solid-phase peptide synthesis. Methods Enzymol 289: 3-13, 1997
Merrifield, R. B.: Solid phase peptide synthesis. I. the synthesis of a tetrapeptide. J Am Chem Soc 85: 2149-54, 1963
Merrifield, R. B.: Solid-phase peptide synthesis. Adv Enzymol Relat Areas Mol Biol 32: 221-96, 1969
Merrifield, R. B. and Woolley, D. W.: The synthesis of peptides with strepogenin activity. J Am Chem Soc 80: 6635-9, 1958
Norman, R. and Coxon, J. M.: Priciples of organic synthesis, New York, 1993
Olivier, A. R. and Parker, P. J.: Expression and characterization of protein kinase C-delta. Eur J Biochem 200: 805-10., 1991
Peloponese, J. M., Jr., Collette, Y., Gregoire, C., Bailly, C., Campese, D., Meurs, E. F., Olive, D., and Loret, E. P.: Full peptide synthesis, purification, and characterization of six Tat variants. Differences observed between HIV-1 isolates from Africa and other continents. J Biol Chem 274: 11473-8., 1999
Qian, Y. W., Wang, Y. C., Hollingsworth, R. E., Jr., Jones, D., Ling, N., and Lee, E. Y.: A retinoblastoma-binding protein related to a negative regulator of Ras in yeast. Nature 364: 648-52., 1993
Sahm, U. G., Olivier, G. W., Branch, S. K., Moss, S. H., and Pouton, C. W.: Synthesis and biological evaluation of alpha-MSH analogues substituted with alanine. Peptides 15: 1297-302, 1994
Sarkadi, B. and Muller, M.: Search for specific inhibitors of multidrug resistance in cancer. Semin Cancer Biol 8: 171-82., 1997
Sarkadi, B., Muller, M., Homolya, L., Hollo, Z., Seprodi, J., Germann, U. A., Gottesman, M. M., Price, E. M., and Boucher, R. C.: Interaction of bioactive hydrophobic peptides with the human multidrug transporter. Faseb J 8: 766-70, 1994
Sharma, R. C., Inoue, S., Roitelman, J., Schimke, R. T., and Simoni, R. D.: Peptide transport by the multidrug resistance pump. J Biol Chem 267: 5731-4, 1992
Sharom, F. J., Lu, P., Liu, R., and Yu, X.: Linear and cyclic peptides as substrates and modulators of P- glycoprotein: peptide binding and effects on drug transport and accumulation. Biochem J 333: 621-30., 1998
Sharom, F. J., Yu, X., DiDiodato, G., and Chu, J. W.: Synthetic hydrophobic peptides are substrates for P-glycoprotein and stimulate drug transport. Biochem J 320 ( Pt 2): 421-8, 1996
Sharom, F. J., Yu, X., Lu, P., Liu, R., Chu, J. W., Szabo, K., Muller, M., Hose, C. D., Monks, A., Varadi, A., Seprodi, J., and Sarkadi, B.: Interaction of the P-glycoprotein multidrug transporter (MDR1) with high affinity peptide chemosensitizers in isolated membranes, reconstituted systems, and intact cells. Biochem Pharmacol 58: 571-86., 1999
Sheehan, J. C. and Hess, G. P.: A new method of forming peptide bonds. J Am Chem Soc 77: 1067-8, 1955
Sucholeiki, I.: New developments in solid phase synthesis supports. Mol Divers 4: 25-30, 1998
Tam, J. P.: Synthetic peptide vaccine design: synthesis and properties of a high-density multiple antigenic peptide system. Proc Natl Acad Sci U S A 85: 5409-13, 1988
Vigneaud, V. d., Ressler, C., Swan, J. M., Roberts, C. W., Katsoyannis, P. G., and Gordon, S.: The synthesis of an octapeptide amide with the hormonal activity of oxytocin. J Am Chem Soc 75: 4879-80, 1953
Wieland, T. and Bernhard, H.: Die verwendung von annydriden aus n-acylierten aminosauren und derivaten anorganischer sauren. Liebigs Ann. Chem. 572: 190-4, 1951
Wieland, T., Schafer, W., and Bokelmann, E.: Uber eine bequeme darstellungsweise von Acylthiophenolen und ihre verwendung zu amid- und peptide-synthesen. Liebigs. Ann. Chem. 573: 99-104, 1951
Yusa, K. and Tsuruo, T.: Reversal mechanism of multidrug resistance by verapamil: direct binding of verapamil to P-glycoprotein on specific sites and transport of verapamil outward across the plasma membrane of K562/ADM cells. Cancer Res 49: 5002-6., 1989
Zervas, L., Borovas, D., and Gazis, E.: New methods in peptide synthesis. I. tritylsulfenyl and o-nitrophenylsulfenyl groups as N-protecting groups. J Am Chem Soc 85: 3660-6, 1963
林岳民: 碩士論文 Effect of peptide(ALLN) on the transport of etoposide in rar small intestine. Institute of Clinical Pharmacy, National Cheng Kung University, Tainan: Taiwan, R.O.C, 1999
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