跳到主要內容

臺灣博碩士論文加值系統

(44.192.38.248) 您好!臺灣時間:2022/11/30 23:00
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

我願授權國圖
: 
twitterline
研究生:林明濬
論文名稱:反撲試劑六甲基二矽硫醚在化學轉換上之應用暨木酚素與新穎鉑類化合物作為新型抗癌藥物之研發
論文名稱(外文):Application of Hexamethyldisilathiane as a Counterattack Reagent in Chemical Transformations and Development of Lignans and Novel Platinum Complexes as New Anticancer Agents
指導教授:胡紀如
學位類別:博士
校院名稱:國立清華大學
系所名稱:化學系
學門:自然科學學門
學類:化學學類
論文種類:學術論文
論文出版年:2007
畢業學年度:95
語文別:英文
論文頁數:98
中文關鍵詞:反撲試劑六甲基二矽硫醚木酚素新穎鉑類化合物抗癌
外文關鍵詞:counterattack reagentHexamethyldisilathianeLignanNovel Platinum Complexesanticancer
相關次數:
  • 被引用被引用:0
  • 點閱點閱:205
  • 評分評分:
  • 下載下載:0
  • 收藏至我的研究室書目清單書目收藏:1
在本論文中,我報告以反撲試劑六甲基二矽硫醚應用於新穎雙官能基轉換之反應。同時,我亦從事木酚素之糖類衍生物與新穎鉑類藥物作為新型抗癌藥物之研究。
在論文的第一部份裡,我建立了一系列的新奇雙官能基轉換反應。此類反應可將硝基環烯於同平反應中轉化成含烯酯基之氰類化合物,其操作手續簡便但涉及之反應之反應機構卻極為複雜。利用此反應亦可合成出高產率的各式α取代之肟類化合物,在這些高效率的反應中運用六甲基二矽硫醚作為一反撲試劑。此類α取代之肟類化合物在不同的反應條件下進行官能基轉換,可得到三種特殊的雙官能基產物。
在第二部份中,我利用八羰基保護之麥芽糖及三氟化硼於二氯甲烷中與三甲基木酚素反應,在去保護後,得到具麥芽糖官能基之木酚素衍生物,此類衍生物的水溶性佳,經由與六種人類癌症細胞進行反應與動物體內實驗測試後,我們發現此類木酚素衍生物確實具有抑制癌細胞生長之活性,同時也具備了低毒性的特性。
在第三部份中,我利用具吸光團的氮類雜環及多種亞砜於水中與四氯二鉀鉑進行反應,以合成六個新型鉑類化合物,經由與人類舌癌細胞Cal27進行反應,我們發現此類鉑類化合物確實具有抗癌活性,並利用此抗癌活性的結果比較其官能基與活性之間的構效關係。
In this thesis, I report the application of “counterattack reagent” hexamethyldisilathiane on the accomplish of a series of novel double functional group transformations. Furthermore, I synthesize the derivatives of nordihydroguaiaretic acid (NDGA) and novel platinum complexes as a new anticancer agents.
In Part 1 of this thesis, a series of novel double functional group transformations were established. These transformations convert nitrocycloalkenes to ��-substituted ketoximes in “one flask” procedure. Sophisticated mechanisms are involved in these reactions. In those efficient tandem processes, hexamethyldisilathiane acts as a counterattack reagent.
In Part 2 of this thesis, water soluble derivatives of nordihydroguaiaretic acid (NDGA), Malotse-M3N, was synthesized by coupling tri-O-methyl-NDGA (M3N) with maltose in the presence of boron trifluoride-diethyl etherate in CH2Cl2 and deprotection by use of sodium methoxide. Maltose-M3N inhibits the growth of the five human cancer cell lines in vitro with IC50 values of 20 �嵱 to 40 �嵱. Nevertheless, inhibition of CDC2 and survivin expression is observed. Four daily intratumoral injections of Malotse-M3N into C3 tumors also effectively suppresses CDC2 and survivin expression and induces apoptosis throughout the whole tumor tissues without toxicities.
In Part 3 of this thesis, A series of novel organoplatinum complexes were synthesized by adding sodium 2-mercaptopyridine N-oxide and a series of sulfoxides to K2PtCl4 in DMF and H2O (1 : 5) condition. In vitro growth inhibitory effect of those organoplatinum complexes were evaluated in human cancer cell lines Cal27. We found five of those organoplatinum complexes exhibited noteworthy anticancer activity.
Contents
English Abstract ……………………………………………………………….. i
Chinese Abstract …………..………………………………………………….. iii
Acknowledgement …………………………………………………………….. iv
Contents ……………………………………………………………………….. v
Introduction …………………………………………………………….. 1
Part 1: Novel Double Functional Group Transformations: Conversion of Nitrocycloalk-
enes to ketoximes, ��-Substituted Lactams, and ��,��-Unsaturated Cyanoalkenylates
by Use of Hexamethyldisilathiane …….…………......…………………..… 2
Abstract ………………………………………………………………… 3
Introduction …………………………………………………………….. 4
Results ……………………...…………...……………………………… 6
Discussion ……………………………………………………………… 11
Conclusion …..………………………………………………………… 15
Experimental Section …………………………………………………. 16
References …………………………………………………………….. 25
Part 2: Design and Synthesis of Highly Water Soluble Nordihydroguaiaretic Acid Deri-
vatives as Anticancer Agents ……………..……………….…….. 27
Abstract …………………………………………………..…………… 28
Introduction ……………………………………………….…………... 29
Results ……………………...…………...………………..…………… 31
Discussion ………………………………………………..…………… 40
Conclusion …..………………………………………………………… 42
Experimental Section …………………………………………………. 43
References …………………………………………………………….. 49
Part 3: Design and Synthesis of Novel Platinum Derivatives as Anticancer Agent ….. 51
Abstract …………………………………………………..…………… 52
Introduction ……………………………………………….…………... 53
Results ……………………...…………...………………..…………… 55
Discussion ………………………………………………..…………… 60
Conclusion …..………………………………………………………… 61
Experimental Section …………………………………………………. 62
References …………………………………………………………….. 67
Spectra ………………………………….………...…………………………………….. 69
1. Eschenmoser, A.; Felix, D.; Ohloff, G. Helv. Chim. Acta 1967, 50, 719–723.
2. Hwu, J. R.; Tsay, S.-C.; King, K. Y.; Horng, D.-N. Pure Appl. Chem. 1999, 71, 445–451.
3. Hwu, J. R.; Gilbert, B. A. Tetrahedron 1989, 45, 1233.
4. Hwu, J. R.; Tsay, S.-C. Chem. Commun. 1998, 2, 161–168.
5. Hwu, J. R.; Lin, C.-F.; Tsay, S.-C. Phosphorus, Sulfur, Silicon, Relat. Elem. 2005, 180, 1389–1393.
6. Matulenko, M. A. In Encyclopedia of Reagents for Organic Synthesis; Paquette, L. A., Ed.; Wiley: Chichester, 1995; Vol. 1, p 608.Michel, D.; Schlosser, M. Synthesis 1996, 1007.
7. Degl’Innocenti, A.; Capperucci, A.; Castagnoli, G.; Malesci, I. Synlett. 2005, 13, 1965–1983.
8. Degl'Innocenti, A.; Capperucci, A.; Cerreti, A.; Pollicino, S.; Scapecchi, S.; Malesci, I.; Castagnoli, G. Synlett. 2005, 20, 3063–3066.
9. Degl’Innocenti, A.; Capperucci, A.; Malesci, I.; Castagnoli, G. Tetrahedron Lett. 2005, 46, 4711–4713.
10. Kamal, A.; Reddy, K. L.; Reddy, G. S. K.; Reddy, B. S. N. Tetrahedron Lett. 2004, 45, 3499–3501.
11. Hwu, J. R.; Tsay, S.-C. Tetrahedron 1990, 46, 7413–7428.
12. Tsay, S.-C.; Gani, P.; Hwu, J. R. J. Chem. Soc., Perkin Trans. 1 1991, 6, 1493–1495.
13. Hwu, J. R.; Wang, N. J. Chem. Soc., Chem. Commun. 1987, 6, 427–428.
14. Tso, H.-H.; Gilbert, B. A.; Hwu, J. R. J. Chem. Soc., Chem. Commun. 1993, 8, 669–670.
15. Corey, E. J.; Estreicher, H. J. Am. Chem. Soc. 1978, 100, 6294–6295.
16. Jew, S.-S.; Kim, H.-D.; Cho, Y.-S.; Cook, C.-H. Chem. Lett.1986, 1747.
17. Narayanan, C. R.; Parker, M. S.; Wadia, M. S. Tetrahedron Lett. 1970, 54, 4703–4705.
18. Kornblum, N. Org. React. 1962, 12, 101–156.
19. Barrett, A. G. M. Chem. Soc. Rev. 1991, 20, 95.
20. Perekalin, V. V.; Lipina, E. S.; Berestovitskaya, V. M.; Efremov, D. A. Nitroalkenes; Wiley: Chichester, 1994; Chapter 1.
21. Hwu, J. R.; Chen, K.-L.; Ananthan, S. J. Chem. Soc., Chem. Commun. 1994, 12,1425–1426.
22. Fiorenza, M.; Reginato, G.; Ricci, A.; Taddei, M. J. Org. Chem. 1984, 49, 551–553.
23. Weber, W. P. Silicon Reagents for Organic Synthesis; Springer–Verlag: New York, 1983; p 339.
24. Soysa, H. S. D.; Weber, W. P. Tetrahedron Lett. 1978, 62, 235.
25. Brook, A. G.; Bassindale, A. R. In Rearrangements in Ground and Excited States; de Mayo, P., Ed.; Academic: New York, 1980; Vol. 2, Essay 9.
26. Hiroi, K.; Otsuka, M.; Sato, S. Chem. Lett. 1985, 12, 1907–1910.
1. Waller, C. W.; Gisvold, O. J. Amer. Pharm. Ass., Sci. Ed. 1945, 34, 78.
2. Setchell, K. D.; Axelson, M. Nature 1980, 287, 740.
3. Trang, T.; Stutak, M.; Quirion, R.; Jhamandas, K. Br. J. Pharmacol. 2003, 140, 295–304.
4. Nakadate, T. Jpn. J. Pharmacol. 1989, 49, 1–9.
5. Hausott, B.; Greger, H.; Marian, B. J. Cancer Res. Clin. Oncol. 2003, 129, 569–576.
6. Fujiwara, T.; Misumi, Y.; Ikehara, Y. Biochem. Biophys. Res. Commum. 2003, 301, 927–933.
7. (a) Cheng, J. S.; Jan, C. R. Toxicol. In Vitro 2002, 16, 485–490. (b) Wang, J. L.; Chang, H. J.; Tseng, L. L.; Liu, C. P.; Lee, K. C.; Chou, K. J.; Cheng, J. S.; Lo, Y. K.; Su, W.; Law, Y. P.; Chen, W. C.; Chan, R. C.; Jan, C. R. Pharmacol. Toxicol. 2001, 89, 301–305. (c) Su, W.; Tseng, L. L.; Lin, M. C.; Chang, H. J.; Lee, K. C.; Chou, K. J.; Lo, Y. K.; Cheng, J. S. Chang, H. T.; Wang, J. L.; Liu, C. P.; Chen, W. C.; Jan, C. R. Neurochem. Int. 2002, 40, 249–254. (d) Huang, J. K.; Chen, W. C.; Huang, C. J.; Hsu, S. S.; Chen, J. S.; Cheng, H. H.; Chang, H. T.; Jiann, B. P.; Jan, C. R. Life Sciences 2004, 75, 2341–2351.
8. Yamamura, H.; Nagano, N.; Hirano, M.; Muraki, K.; Watanabe, M. Imaizumi, Y. J. Pharmacol. Exp. Ther. 1999, 291, 140–146.
9. Ono, K.; Hasegawa, K.; Yoshiike, Y.; Takashima, A.; Yamada, M.; Naiki, H. J. Neurochem. 2002, 81, 434–440.
10. Lee, C. H.; Jang, Y. S.; Her, S. J.; Moon, Y. M.; Baek, S. J.; Eling, T. Exp. Cell. Res. 2003, 289, 335–341.
11. Hwu, J. R.; Tseng, W. N.; Gnabre, J.; Giza, P.; Huang, R. C. J. Med. Chem. 1998, 41, 2994–3000.
12. Huang, R. C.; Li, Y.; Giza, P. E.; Gnabre, J. N.; Abd-Elazem, I. S.; King, K. Y.; Hwu, J. R. Antiviral Res. 2003, 58, 57–64.
13. King, K. Y.; Hakimelahi, G. H.; Huang, R. C.; Hwu, J. R. J . Genetics Mol. Biol. 2002, 13, 248–257.
14. Gnabre, J. N.; Brady, J. N.; Clanton, D. J.; Ito, Y.; Dittmer, J.; Bates, R. B.; Huang, R. C. Proc. Natl. Acad. Sci. USA 1995, 92, 11239–11243.
15. Gnabre, J.; Ito, Y.; Ma, Y.; Huang, R. C. J. Chromatogr. A 1996, 719, 353–364
16. Chen, H.; Teng, L.; Li, J.; Park, R.; Mold, D. E.; Gnabre, J.; Hwu, J. R.; Tseng, W. N.; Huang, R. C. J. Med. Chem. 1998, 41, 3001–3007.
17. Park, R.; Giza, P. E.; Mold, D. E.; Huang, R. C. Antiviral Res. 2003, 58, 35–45.
18. Craigol, J.; Callahan, M.; Huang, R. C.; DeLucia, A. Antiviral Res. 2000, 47, 19–28.
19. Chang, C.-C.; Heller, J. D.; Kuo, J.; Huang, R. C. Proc. Natl. Acad. Sci. USA 2004, 101, 13239–13244.
20. Heller, J. D.; Kuo, J.; Wu, T. C.; Kast, W. M.; Huang, R. C. Cancer Res. 2001, 61, 5499–5504.
21. McKelvy, J. F.; Lee, Y. C. Arch. Biochem. Biophys. 1969, 132, 99-110.
22. Mabic, S.; Benezra, C.; Lepoittevin, J. P. Tetrahedron Lett. 1993, 34, 4531-4534.
1. Lebwohl, D.; Canetta, R. Eur. J. Cancer 1998, 34, 1522–34.
2. Weiss, R. B.; Christian, M. C. Drugs 1993, 46, 360–77.
3. Trimmer, E. E.; Essigmann, J. M. Essays Biochem. 1999, 34, 191.
4. Wong, E.; Giandomenico, C. M. Chem. Rev. 1999, 99, 2451.
5. Guo, Z.; Sadler, P. J. Angew. Chem. Int. Ed. 1999, 38, 1512.
6. For reviewers, see: (a) Reedijk, J. J. Chem. Soc., Chem. Commun. 1996, 801; (b) Fuertes, M. A.; Alonso, C.; Perez, J. M. Chem. Rev. 2003, 103, 645; (c) Chupin, V.; de Kroon, A. I. P. M.; de Kruijff, B.; J. Am. Chem. Soc. 2004, 126, 13816; (d) Mandal, R.; Kalke, R.; Li, X.-F. Chem. Res. Toxicol. 2004, 17, 1391; (e) Tacka, K. A.; Dabrowiak, J. C.; Goodisman, J.; Penefsky, H. S.; Souid, A.-K. Chem. Res. Toxicol. 2004, 17, 1297; (f) Tacka, K. A.; Dabrowiak, J. C.; Goodisman, J.; Penefsky, H. S.; Souid, A.-K. Chem. Res. Toxicol. 2004, 17, 1102 (g) Tacka, K. A.; Szalda, D.; Souid, A.-K.; Goodisman, J.; Dabrowiak, J. C. Chem. Res. Toxicol. 2004, 17, 1434; (h) Pasetto, L. M. 2006, 60, 59–75.
7. For recent development, see: (a) Okada, T.; El-Mehasseb, I. M.; Kodaka, M.; Tomohiro, T.; Okamoto, K.; Okuno, H. J. Med. Chem. 2001, 44, 4661; (b) Pors, K.; Paniwnyk, Z.; Ruparelia, K. C.; Teesdale-Spittle, P. H.; Hartley, J. A.; Kelland, L. R.; Patterson, L. H. J. Med. Chem. 2001, 47, 1856; (c) Jansen, B. A. J.; Wielaard, P.; Dulk, H. D; Brouwer, J.; Reedijk J. Eur. J. Inorg. Chem. 2002, 2375; (d) Deubel, D. V. J. Am. Chem. Soc. 2002, 124, 5834; (e) Baik, M.-H.; Friesner, R. A.; Lippard, S. J. J. Am. Chem. Soc. 2003, 125, 14082; (f) Zak, F.; Turanek, J.; Kroutil, A.; Sova, P.; Mistr, A.; Poulova, A.; Mikolin, P.; Zak, Z.; Kasna, A.; Zaluska, D.; Neca, J.; Sindlerova, L.; Kozubik, A. J. Med. Chem. 2004, 47, 761; (g) Deubel, D. V. J. Am. Chem. Soc. 2004, 126, 5999; (h) Zak, F.; Turanek, J.; Kroutil, A.; Sova, P.; Mistr, A.; Poulova, A.; Mikolin, P.; Zak, Z.; Kasna, A.; Zaluska, D.; Neca, J.; Sindlerova, L.; Kozubik, A. J. Med. Chem. 2004, 46 761; (i) Komeda, S.; Kalayda, G. V.; Lutz, M.; Spek, A. L.; Yamanaka, Y.; Sato, T.; Chikuma, M.; Reedijk, J. J. Med. Chem. 2004, 46 1210; (j) Mitkova, E.; Ugrinova, I.; Pashev, I. G.; Pasheva, E. A. Biochemistry 2005, 44, 5893; (k) Criado, J. J.; Fernandez, E. R.; Manzano, J. L.; Alonso, A.; Barrena, S.; Medarde, M.; Pelaez, R.; Tabernero, M. D.; Orfao, A. Bioconjugate Chem. 2005, 16, 275; (l) Liu, X.; Shen, H.; Zhu, H. B.; Cui, K.; Gou, S. H. Bioorg. Med. Chem. Lett. 2007, 17, 3831–3834.
8. Lu, K. L.; Hwu, J. R.; Tsay, S. C.; Yu, S. F.; Hung, J. T.; Huang, J. J. U. S. Patent US 6 458 833 B1 2002.
9. Alderden, R. A.; Mellor, H. R.; Modok, S.; Hambley, T. W.; Callaghan, R. Biochem. Pharmacol. 2007, 71, 1136–1145.
QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top