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研究生:李毓寰
研究生(外文):Yu-Huan Lee
論文名稱:斑蝥胺素衍生物的合成與細胞毒性之探討
論文名稱(外文):Synthesis and Cytotoxicity of Cantharidinimide Dimers and Imide Analogues
指導教授:林本元林本元引用關係
指導教授(外文):Pen-Yuan Lin
學位類別:碩士
校院名稱:臺北醫學大學
系所名稱:藥學系
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2005
畢業學年度:93
語文別:中文
論文頁數:94
中文關鍵詞:斑蝥素
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斑蝥為翹翅目芫青科斑芫青屬的昆蟲,主要成分為斑蝥素 (Cantharidin; exo,exo-2,3-Dimethyl- 7-oxabicyclo [2,2,1] heptane-2,3-dicarboxylic anhydride),研究中指出斑蝥素具有發泡、抗腫瘤的作用,或當作除草劑、殺蟲劑、毛髮生長刺激劑,目前臨床上則用於治療原發性肝癌及傳染性疣。本研究合成兩系列之斑蝥胺素衍生物,一方面以斑蝥素與烷基雙胺為原料,在鹼性環境下高溫封管反應兩小時,冷卻至室溫後進行脫水反應,經由薄層層析法及再結晶可得到一系列斑蝥胺素雙體衍生物,另一方面以斑蝥胺素為起始物,與活化之氮丙啶合成衍生物。此外亦有使用醯亞胺類與活性之氮丙啶反應,得到一系列衍生物,再經由核磁共振儀、紅外光光譜儀、高解析度質譜儀確定結構,並進行細胞毒性試驗。
Mylabris phalerata, Meloidae family of Coleoptera, has been known since antiquity to produce a potent toxic defensive agent, known as cantharidin (exo,exo-2,3-dimethyl-7-oxabicyclo [2.2.1] heptane-2,3- dicarboxylic anhydride), but well-known as Spanish Fly. In the past, Cantharidin has used as anticancer, herbicidal, pesticide and treatment of hepatic carcinoma and molluscum contagiosum activities.We used cantharidin and serious of diaminoalkane as starting materials, by heating 200℃ in sealed tube to form various cantharidinimide dimer. The other hand, we utilized various N-activated aziridine derivatives as starting materials, reacted with cantharidinimide and different imide analogous to obtain serial derivatives. All of the products were measured by 1H-NMR, IR, High-resolution mass spectrometry. In addition, we evaluated these compounds in cytotoxicity.
目錄

頁次
目錄…………………………………………………………………………………..I
流程目錄……………………………………………………………………………III
附表目錄…………………………………………………………………………….IV
附圖目錄……………………………………………………………………………..V
中文摘要……………………………………………………………………………...1
英文摘要……………………………………………………………………………...2
壹、緒論……………………………………………………………………………..3
一、研究背景……………………………………………………………………3
二、研究目的……………………………………………………………………6
貳、結果與討論…………………………………………………………………….11
一、化學合成……………………………………………………………………11
(一) Cantharidin原料之製備………………………………………………11
(二) 斑蝥胺素 (Cantharidinimide) 衍生物之合成……………………….15
1. Cantharidinimide dimer 衍生物之合成……………………...……16
2. Imide analogue 衍生物之合成……………………………………19
二、生物活性……………………………………………………………………23
參、實驗部分……………………………………………………………………….24
一、儀器與試藥……………………………………………………………..24
(一) 實驗儀器…………………………………………………………..24
(二) 試藥及試劑…………………………………………………………25
(三) 材料…………………………………………………………………26
二、化學合成部分…………………………………………………………….27
(一) Cantharidin原料之製備…………………………………………….27
(二) 斑蝥胺素及其類似物之合成步驟…………………………………28
三、生物活性部分…………………………………………………………….45
(一) 細胞及培養基………………………………………………………45
(二) MTT細胞存活率試驗……………………………………………..46
肆、結論……………………………………………………………………………47
伍、參考文獻………………………………………………………………………50
陸、附圖目錄………………………………………………………………………54









流程目錄

頁次
Scheme 1. Synthesis of cantharidinimide dimer and imide analogue derivatives…...10
Scheme 2. Total synthesis of deoxycantharidin by Woodward……………………...12
Scheme 3. The stereospecific synthesis of cantharidin by Stork…………………….12
Scheme 4. The synthesis of cantharidin via Diels-Alder reaction by Dauben………13
Scheme 5. Preparation of cantharidin……………………………………………….13
Scheme 6. Mechanism of Synthesis of Cantharidinimide dimer derivatives….…….15
Scheme 7. Mechanism of Synthesis of Imide analogue derivatives…………………16
Scheme 8. Synthesis of cantharidinimide dimmer derivatives (A)……...…………..16
Scheme 9. Synthesis of cantharidinimide dimmer derivatives (B)…………...……..17
Scheme 10. Imide analogue derivates……………………………………………….20
Scheme 11. Reaction mechanism of method B………….…………………………..47












附表目錄

頁次
Table 1. The chemical and physical data of cantharidinimide dimmer derivatives….18
Table 2. The chemical and physical data of imide analogue derivates……...…21
Table 3. Cytotoxicities of cantharidinimide analogues and related compounds in human breast adenocarcinoma cell line…………………………………….24


















附圖目錄

頁次
Fig 1. 1H-NMR spectrum of cantharidin (CDCl3, 500MHz)………………..………55
Fig 2. 1H-NMR spectrum of compound 1 (CDCl3, 500MHz)………………………56
Fig 3. HRMS spectrum of compound 1……………………...………………………57
Fig 4. 1H-NMR spectrum of compound 2 (CDCl3, 500MHz)………...…………….58
Fig 5. IR spectrum of compound 2 (KBr)……………………..…………………….59
Fig 6. HRMS spectrum of compound 2……………………….…………………….60
Fig 7. 1H-NMR spectrum of compound 3 (CDCl3, 500MHz)………...…………….61
Fig 8. HRMS spectrum of compound 3……………………………………………...62
Fig 9. 1H-NMR spectrum of compound 4 (CDCl3, 500MHz)………………………63
Fig 10. HRMS spectrum of compound 4…………………………….…...………….64
Fig 11. 1H-NMR spectrum of compound 5 (CDCl3, 500MHz)……………………..65
Fig 12. IR spectrum of compound 5 (KBr)………………………………………….66
Fig 13. 1H-NMR spectrum of compound 6(CDCl3, 500MHz)…….………………..67
Fig 14. IR spectrum of compound 6 (KBr)………………………………………….68
Fig 15. 1H-NMR spectrum of compound 7 (CDCl3, 500MHz)……….…………….69
Fig 16. HRMS spectrum of compound 7…………………………………………….70
Fig 17. 1H-NMR spectrum of compound 8(CDCl3, 500MHz)……………………...71
Fig 18. 1H-NMR spectrum of compound 9 (CDCl3, 500MHz)……………………..72
Fig 19. HRMS spectrum of compound 9…………………………………………….73

Fig 20. 1H-NMR spectrum of compound 10 (CDCl3, 500MHz)………...………….74
Fig 21. HRMS spectrum of compound 10……………………………..…………….75
Fig 22. 1H-NMR spectrum of compound 11 (CDCl3, 500MHz)……………..……..76
Fig 23. IR spectrum of compound 11 (KBr)………………………..………………..77
Fig 24. HRMS spectrum of compound 11………………………...…………………78
Fig 25. 1H-NMR spectrum of compound 12 (CDCl3, 500MHz)…………..………..79
Fig 26. HRMS spectrum of compound 12…………………...………………………80
Fig 27. 1H-NMR spectrum of compound 13 (CDCl3, 500MHz)……………………81
Fig 28. HRMS spectrum of compound 13…………….……………………………..82
Fig 29. 1H-NMR spectrum of compound 14 (CDCl3, 500MHz)……………………83
Fig 30. HRMS spectrum of compound 14…………………………………………...84
Fig 31. 1H-NMR spectrum of compound 15 (CDCl3, 500MHz)……………………85
Fig 32. IR spectrum of compound 15 (KBr)………………………………………...86
Fig 33. HRMS spectrum of compound 15…………………………………………...87
Fig 34. 1H-NMR spectrum of compound 16 (CDCl3, 500MHz)……………………88
Fig 35. IR spectrum of compound 16 (KBr)………………………………………...89
Fig 36. HRMS spectrum of compound 16…………….……………………………..90
Fig 37. 1H-NMR spectrum of compound 17 (CDCl3, 500MHz)……………………91
Fig 38. HRMS spectrum of compound 17…………………………………………...92
Fig 39. 1H-NMR spectrum of compound 18 (CDCl3, 500MHz)……………………93
Fig 40. HRMS spectrum of compound 18…………………………………………...94
伍、參考文獻

1.張蘭昌,斑蝥,中藥大辭典,1981,3733-3735。
2.李時珍,斑蝥,重訂本草綱目,1994,40卷,1287-1288。
3.黃三元,斑蝥,本草備要新編,1990,507-508。
4.Yosef, R.; Carrel, J. E.; Eisner, T. Contrasting Reactions of Loggerhead Shirkes to Two Type of Chemistry Defended Insect Prey. J. Chem. Ecol., 1996, 22, 173-181.
5.Yell., J. A.; Burge, S. M.; Dean D. Cantharidin-induced acantholysis in Darier’s disease: does acantholysis initiate dyskeratosis? Brit. J. Dermatol., 1994, 313, 40-47.
6.Silverberg, N. B.; Sidury, R.; Mancini, J. Childhood molluscum contagiosum: Experience with cantharidin therapy in 300 patients. J. Am. Acad. Dermatol., 2000, 43, 503-507.
7.Masafumi, M.; Graziano, M.J.; Casida, E. Endothal and Cantharidin Analogues: Relation of Structure to Herbicidal Activity and Mammalian Toxicity. J. Agr. Food Chem., 1987, 35, 823-829.
8.Honkanen, R. E. Cantharidin, another natural toxin that inhibits the activity of serine/threonine protein phosphatases type 1 and 2A. FEBS, 1993, 330, 283-286.
9.Eldridge, R.; Casida, J. E. Cantharidin Effects on Protein Phosphatases and the Phosphorylation State of Phosphoproteins in Mice. Toxicol. Appl. Pharm., 1995, 130, 95-100.
10.Laidley, C. W.; Cohen, E.; Casida, J. E. Protein Phosphatase in Neuroblastoma Cells: [3H]Cantharidin Binding Site in Relation to Cytotoxicity. J. Pharmacol. Exp. Ther., 1997, 280, 1152-1158.
11.Sheppeck, J. E.; Gauss, C. M.; Chamberlin, A. R. Inhibition of the Ser-Thr Phosphatases PP1 and PP2A by Naturally Occurring Toxins. Bioorg. Med. Chem., 1997, 5, 1739-1750.
12.Kanpp, J.; Boknik, P.; Lonck, B. The effect of the protein phosphatases inhibitor cantharidin on β-adrenoceptor-mediated vasorelaxation. Brit. J. Pharmacol., 1997, 120, 421-428.
13.Kanpp, J.; Boknik, Huke, S. The mechanism of action of cantharidin in smooth muscle. Brit. J. Pharmacol., 1998, 123, 911-919.
14.Kanpp, J.; Boknik, Luss, I. The Protein Phosphatase Inhibitor Cantharidin Alters Vascular Endothelial Cell Permeability. J. Pharmacol. Exp. Ther., 1999, 189, 1480-1486.
15.Hong, S. J. Inhibition of mouse neuromuscular transmission and contractile function by okadaic acid and cantharidin. Brit. J. Pharmacol., 2000, 130, 1211-1218.
16.Krautheim, A.; Brechlin, P.; Becker, K. Hamster pancreatic beta cell lines with altered sensitivity towards apoptoic signaling by phosphatase inhibitors. Brit. J. Pharmacol., 2000, 129, 687-694.
17.Morana, S. J.; Wolf, C. M.; Jason, J. L. The Involvement of Protein Phosphatases in the Activation of ICE/CED-3 Protease, Intracellular Acidification, DNA Digestion, and Apoptosis. J. Biol. Chem., 1996, 271, 18263-18271.
18.Wang, C. C.; Wu, C. H.; Hsieh, K. J. Cytotoxic effects of cantharidin on the growth of normal and carcinoma cells. Toxicology, 2000, 147, 77-87.
19.劉建;高建輝;劉曉秋,班蝥素及其衍生物的研究進展,中藥材,2003,26卷,453-455。
20.Woodward, R. B.; Loftfield, R. B. The Structure of Cantharidine and the Synthesis of Desoxycantharidine. J. Am. Chem. Soc., 1941, 63, 3167-3171.
21.Stork, G.; Tamelen, E. E.; Friedman, L. J.; Burgstahler, A. W. Cantharidin. A Stereospecific Total Synthesis. J. Am. Chem. Soc., 1951, 73, 4501.
22.Stork, G.; Tamelen, E. E.; Friedman, L. J.; Burgstahler, A. W. A Stereospecific Synthesis of Cantharidin. J. Am. Chem. Soc., 1953, 75, 384-392.
23.Dauben, W. G.; Krabbenhoft, H. O. Organic Reactions at High Pressure. J. Am. Chem. Soc., 1976, 98, 1992-1993.
24.Dauben, W. G.; Kessel, C. R.; Takemura, K. H. Simple, Efficient Total Synthesis of Cantharidin via a High-Pressure Diels-Alder Reaction. J. Am. Chem. Soc., 1980, 102, 6893-6894.
25.Sundram, U.N.; Griffin, J.H.; Nicas, T.I.; Novel Vancomycin Dimers with Activity against Vancomycin-Resistant Enterococci. J. Am. Chem. Soc.,1996, 118, 13107-13108.
26.Gary, H. P.; Ik-Hyeon, P.; Surojit, S.; Andrew, J. M.; Kristina, B.; Suji, X.; Theresa, A. S. Orally Active, Antimalarial, Anticancer, Artemisinin-Derived Trioxane Dimers with High Stability and Efficacy J. Med. Chem. 2003, 46, 1060-1065.
27.Wolfgang, O.; Elmar, F. An Enantioselective Synthesis and Absolute Configuration of Natural Pumiliotoxin-C. Helv. Chim. Acta. 1997, 60, 204.
28.Martens, J.; Scheunemann, M. Tetrahedron Lett. 1991, 32, 1417.
29.Prabhsksr, K. J.; Francis, J. W. Synthesis of C2-Symmetric HIV-1 Protease Inhibitors Form D-Mannitol. Bioorg. Med. Chem. Lett. 1992, 2, 353.
30.Tanner, D.; Somfai, P. From Aziridines to Carbapenems via a Novel b-Lactam Ring Closure an Enantioselective Synthesis of PS-5. Tetrahedron. 1988, 44, 619.
31.Tanner, D.; HE, H. M. Enantioselective Routes toward 1b-Methylcarbapenems from Chiral Aziridines Tetrahedron. 1992, 48, 6079.
32.Arroa, S. K.; Structural, M. B. C. Conformational and Theoretical Binding Structure of Antitumor Antibiotic Porfiromycin, a Covalent Binder of DNA, by X-ray, NMR, and Molecular Mechanics. J. Med. Chem. 1990, 33, 3000-3008.
33.Marlon, C.; Stephen, J. B. A Novel Combined Chemical-Enzymatic Synthesis of Cross-Linked DNA Using a Nucleoside Triphosphate Analogue. Biochemistry. 1991, 30, 788-796.
34.Edwin, V.; Naidu, B. N.; Artis, K.; Warner, D. L. Synthetic Enantiopure Aziridinomitosenes: Preparation, Reactivity, and DNA Alkylation Studies. J. Am. Chem. Soc. 2003, 125, 15796-15806.
35.Stefano, A.; Francesco, O.; Robert, S. C. DNA Cross-Linking by Azinomycin B: Monte Carlo Simulations in the Evaluation of Sequence Selectivity. J. Med. Chem. 2002, 45, 861-870.
36.Helsby, N. A.; Wheeler, S. J.; Frederik, B. P. Brain D. Effect of Nitroreduction
on the Alkylating Reactivity and Cytotoxicity of the 2,4-Dinitrobenzamide-5
-aziridine CB 1954 and the Corresponding Nitrogen Mustard SN 23862: Distinct Mechanisms of Boreductive Activation. Chem. Res. Toxicol. 2003, 16, 469-478.
37.Salama, R. B.; Hammouda, Y.; Gassim, I. Isolation of Cantharidin from Cyaneolytta sapphirina. J. Pharm. Pharmacol., 1974, 26, 268-269.
38.Zehnder, M.; Thewalt, U. Struktur von Cantharidin, C10H12O4. Helv. Chim. Acta, 1977, 60, 740-742.
39.Clausen, O. P. F. C.; Kirkhus, B.; Schjoberg, A. R.; Cell Cycle Progression Kinetics of Regenerating Mouse C: An in vivo Study Combining DNA Flow Cytometry, Cell Sorting, and [3H]dThd Autoradiography. J. Invest. Dermatol., 1996, 86, 402-405.
40.Wang, C. C.; Wu, C. H.; Hsieh, K. J.; Yen, K. Y.; Yang, L. L. Cytotoxic Effects of Cantharidin on the Growth of Normal and Carcinoma Cell. Toxicology, 2000, 147, 77-78.
41.Coste, J.; Le-Nguyen, D.; Castro, B. PyBOP®: a New Peptide Coupling Reagent Devoid of Toxic by-product. Tetrahedron Lett., 1990, 31(2), 205-208.
42.Frerot, E.; Coste, J.; Pantaloni, A.; Dufour, MN; Jouin, P. PyBOP® and PyBroP: Two reagents for the Difficult Coupling of the α,α-Dialkyl Amino Acid, Aib. Tetrahedron, 1991, 47(2), 259-270.
43.Coste, J.; Dufour, MN; Pantaloni, A.; Castro, B. BroP: A New Reagent for Coupling N-Methylated Amino Acid. Tetrahedron Lett., 1990, 31(5), 669-672.
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