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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 梁博煌(Po-Huang Liang) | |
| dc.contributor.author | Vathan Kumar | en |
| dc.contributor.author | 庫方昇 | zh_TW |
| dc.date.accessioned | 2021-06-16T03:58:19Z | - |
| dc.date.available | 2015-12-31 | |
| dc.date.copyright | 2014-12-24 | |
| dc.date.issued | 2014 | |
| dc.date.submitted | 2014-11-28 | |
| dc.identifier.citation | Chapter 2 References
1. Lamb R. A., Krug, R.M. Orthomyxoviridae: the viruses and their replication. (ed. D.M. Knipe, Howely, P.M..) (Lippincott Williams and Wilkins, Philadelphia 2001). 2. Watanabe, Y. et al. The changing nature of avian influenza A virus (H5N1). Trends Microbiol 20, 11-20 (2012). 3. Taubenberger, J.K. et al. 1918 Influenza: the mother of all pandemics. Emerg Infect Dis 12, 15-22 (2006). 4. CDC. Key Facts About Avian Influenza (Bird Flu) and Highly Pathogenic Avian Influenza A (H5N1) Virus. (2010 ). 5. Fiebig, L. et al. Avian influenza A(H5N1) in humans: new insights from a line list of World Health Organization confirmed cases, September 2006 to August 2010. Euro Surveill 16 (2011). 6. Herfst, S. et al. Airborne transmission of influenza A/H5N1 virus between ferrets. Science 336, 1534-41 (2012). 7. Osterholm, M.T. et al. Public health and biosecurity. Life sciences at a crossroads: respiratory transmissible H5N1. Science 335, 801-2 (2012). 8. Stevens, J. et al. Structure and receptor specificity of the hemagglutinin from an H5N1 influenza virus. Science 312, 404-10 (2006). 9. Uyeki, T.M. et al. Global concerns regarding novel influenza A (H7N9) virus infections. N Engl J Med 368, 1862-4 (2013). 10. CDC. Avian Influenza A (H7N9) Virus. (2013). 11. Guterl, F. Waiting to explode. Sci Am 306, 64-9 (2012). 12. von Itzstein, M. The war against influenza: discovery and development of sialidase inhibitors. Nat Rev Drug Discov 6, 967-974 (2007). 13. Rey-Carrizo, M. et al. 3-Azatetracyclo[5.2.1.15,8.01,5]undecane Derivatives: From Wild-Type Inhibitors of the M2 Ion Channel of Influenza A Virus to Derivatives with Potent Activity against the V27A Mutant. J Med Chem 56, 9265-9274 (2013). 14. Lamb, R.A. et al.. Influenza virus M2 protein is an integral membrane protein expressed on the infected-cell surface. Cell 40, 627-33 (1985). 15. Taylor, N.R. et al. Molecular Modeling Studies on Ligand Binding to Sialidase from Influenza Virus and the Mechanism of Catalysis. J Med Chem 37, 616-624 (1994). 16. Flashner, M. et al. The interaction of substrate-related ketals with bacterial and viral neuraminidases. Arch Biochem Biophys 221, 188-196 (1983). 17. Chong, A.K.J. et al. Evidence for a sialosyl cation transition-state complex in the reaction of sialidase from influenza virus. Eur J Biochem 207, 335-343 (1992). 18. von Itzstein, M., Thomson, R. Antiviral Strategies (eds. Krausslich, H.-G. & Bartenschlager, R.) 111-154 (Springer Berlin Heidelberg, 2009). 19. von Itzstein, M. et al. Rational design of potent sialidase-based inhibitors of influenza virus replication. Nature 363, 418-423 (1993). 20. Karpf, M. et al. New, Azide-Free Transformation of Epoxides into 1,2-Diamino Compounds: Synthesis of the Anti-Influenza Neuraminidase Inhibitor Oseltamivir Phosphate (Tamiflu). J Org Chem 66, 2044-2051 (2001). 21. Shie, J. J. et al. Synthesis of Tamiflu and its Phosphonate Congeners Possessing Potent Anti-Influenza Activity. J Am Chem Soc 129, 11892-11893 (2007). 22. Lackenby, A. et al. Emergence of resistance to oseltamivir among influenza A(H1N1) viruses in Europe. Euro Surveill 13 (2008). 23. Yen, H.L. et al. Neuraminidase inhibitor-resistant recombinant A/Vietnam/1203/04 (H5N1) influenza viruses retain their replication efficiency and pathogenicity in vitro and in vivo. J Virol 81, 12418-26 (2007). 24. Gubareva, L.V. et al. Comparison of the activities of zanamivir, oseltamivir, and RWJ-270201 against clinical isolates of influenza virus and neuraminidase inhibitor-resistant variants. Antimicrob Agents Chemother 45, 3403-8 (2001). 25. Hai, R. et al. Influenza A(H7N9) virus gains neuraminidase inhibitor resistance without loss of in vivo virulence or transmissibility. Nat Commun 4, 2854 (2013). 26. Sleeman, K. et al. R292K substitution and drug susceptibility of influenza A(H7N9) viruses. Emerg Infect Dis 19, 1521-4 (2013). 27. Li, Q. et al. The 2009 pandemic H1N1 neuraminidase N1 lacks the 150-cavity in its active site. Nat Struct Mol Biol 17, 1266-1268 (2010). 28. Rudrawar, S. et al. Novel sialic acid derivatives lock open the 150-loop of an influenza A virus group-1 sialidase. Nat Commun 1, 113 (2010). 29. Rudrawar, S., Dyason, J.C., Maggioni, A., Thomson, R.J. & Itzstein, M.v. Novel 3,4-disubstituted-Neu5Ac2en derivatives as probes to investigate flexibility of the influenza virus sialidase 150-loop. Bioorg Med Chem 21, 4820-4830 (2013). 30. Rudrawar, S. et al. Synthesis and evaluation of novel 3-C-alkylated-Neu5Ac2en derivatives as probes of influenza virus sialidase 150-loop flexibility. Org Bio Chem 10, 8628-8639 (2012). 31. Brant, M.G. et al.. A Rigid Bicyclic Platform for the Generation of Conformationally Locked Neuraminidase Inhibitors. Org Lett 14, 5876-5879 (2012). 32. An, J. et al. A Novel Small-Molecule Inhibitor of the Avian Influenza H5N1 Virus Determined through Computational Screening against the Neuraminidase. J Med Chem 52, 2667-2672 (2009). 33. Hung, H.-C. et al. Aurintricarboxylic acid inhibits influenza virus neuraminidase. Antivir Res 81, 123-131 (2009). 34. Magano, J. Synthetic approaches to the neuraminidase inhibitors zanamivir (Relenza) and oseltamivir phosphate (Tamiflu) for the treatment of influenza. Chem Rev 109, 4398-438 (2009). 35. Racane, L. et al. Synthesis of new cyano-substituted bis-benzothiazolyl arylfurans and arylthiophenes. Molecules 8, 342-348 (2003). 36. Moreau, F. et al. Discovery of new Gram-negative antivirulence drugs: Structure and properties of novel E. coli WaaC inhibitors. Bioorg Med Chem Lett 18, 4022-4026 (2008). 37. Hinou, H. et al. A strategy for neuraminidase inhibitors using mechanism-based labeling information. Chem Asian J 6, 1048-56 (2011). 38. Ryu, Y.B. et al. Pterocarpans and flavanones from Sophora flavescens displaying potent neuraminidase inhibition. Bioorg Med Chem Lett 18, 6046-9 (2008). 39. Xie, Y.C. et al. Caffeic acid derivatives: A new type of influenza neuraminidase inhibitors. Bioorg Med Chem Lett 23, 3556-3560 (2013). 40. Sleeman, K. et al. R292K Substitution and Drug Susceptibility of Influenza A(H7N9) Viruses. Emerg Infect Dis 19, 1521-1524 (2013). 41. Wang, Y.T. Insights from modelling the 3D structure of the 2013 H7N9 influenza A virus neuraminidase and its binding interactions with drugs. Med chem comm 4, 1370-1375 (2013). Chapter 3 References 1. Drosten, C. et al. Identification of a Novel Coronavirus in Patients with Severe Acute Respiratory Syndrome. N Engl J Med 348, 1967-1976 (2003). 2. Fouchier, R.A.M. et al. Aetiology: Koch's postulates fulfilled for SARS virus. Nature 423, 240-240 (2003). 3. Ksiazek, T.G. et al. A Novel Coronavirus Associated with Severe Acute Respiratory Syndrome. N Engl J Med 348, 1953-1966 (2003). 4. Lee, N. et al. A Major Outbreak of Severe Acute Respiratory Syndrome in Hong Kong. N Engl J Med 348, 1986-1994 (2003). 5. Peiris, J.S.M. et al. Coronavirus as a possible cause of severe acute respiratory syndrome. Lancet Infect Dis 361, 1319-1325 (2003). 6. Barnard, D.L. et al. Recent developments in anti-severe acute respiratory syndrome coronavirus chemotherapy. Future Virol 6, 615-631 (2011). 7. WHO. Coronavirus never before seen in humans is the cause of SARS (2003). 8. Rota, P.A. et al. Characterization of a novel coronavirus associated with severe acute respiratory syndrome. Science 300, 1394-9 (2003). 9. Spaan, W.J.M., Cavanagh, D. Coronaviridae, in virus taxonomy, VIIIth report of the ICTV. Elsevier Academic Press, London; 945-962 (London 2004). 10. Thiel, V. et al. Mechanisms and enzymes involved in SARS coronavirus genome expression. J Gen Virol 84, 2305-15 (2003). 11. Thiel, V. et al. Viral replicase gene products suffice for coronavirus discontinuous transcription. J Virol 75, 6676-81 (2001). 12. Narayanan, K. et al. Characterization of the coronavirus M protein and nucleocapsid interaction in infected cells. J Virol 74, 8127-34 (2000). 13. Opstelten, D.J. et al. Envelope glycoprotein interactions in coronavirus assembly. J Cell Biol 131, 339-49 (1995). 14. Buchholz, U.J. et al. Contributions of the structural proteins of severe acute respiratory syndrome coronavirus to protective immunity. Proc Natl Acad Sci U S A 101, 9804-9 (2004). 15. Hon, C.C. et al. Evidence of the recombinant origin of a bat severe acute respiratory syndrome (SARS)-like coronavirus and its implications on the direct ancestor of SARS coronavirus. J Virol 82, 1819-26 (2008). 16. Chen, W. et al. SARS-associated coronavirus transmitted from human to pig. Emerg Infect Dis 11, 446-8 (2005). 17. Li, W. et al. Bats are natural reservoirs of SARS-like coronaviruses. Science 310, 676-9 (2005). 18. Wang, L.F. et al. Bats, civets and the emergence of SARS. Curr Top Microbiol Immunol 315, 325-44 (2007). 19. Peiris, J.S. et al. The severe acute respiratory syndrome. N Engl J Med 349, 2431-41 (2003). 20. Fielding, B.C. Human coronavirus NL63: a clinically important virus? Future Microbiol 6, 153-9 (2011). 21. Cui, L.J. et al. Human Coronaviruses HCoV-NL63 and HCoV-HKU1 in Hospitalized Children with Acute Respiratory Infections in Beijing, China. Adv Virol 2011, 129134 (2011). 22. Zaki, A.M. et al. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med 367, 1814-20 (2012). 23. de Groot, R.J. et al. Middle East respiratory syndrome coronavirus (MERS-CoV): announcement of the Coronavirus Study Group. J Virol 87, 7790-2 (2013). 24. Guo, R.T. et al. A molecular ruler for chain elongation catalyzed by octaprenyl pyrophosphate synthase and its structure-based engineering to produce unprecedented long chain trans-prenyl products. Biochemistry 43, 7678-86 (2004). 25. Yang, H. et al. The crystal structures of severe acute respiratory syndrome virus main protease and its complex with an inhibitor. Proc Natl Acad Sci U S A 100, 13190-5 (2003). 26. Anand, K. et al. Coronavirus main proteinase (3CLpro) structure: basis for design of anti-SARS drugs. Science 300, 1763-7 (2003). 27. Hsu, M.F. et al. Mechanism of the maturation process of SARS-CoV 3CL protease. J Biol Chem 280, 31257-66 (2005). 28. Anand, K. et al. Coronavirus Main Proteinase (3CLpro) Structure: Basis for Design of Anti-SARS Drugs. Science 300, 1763-1767 (2003). 29. Lindner, H.A. et al. The papain-like protease from the severe acute respiratory syndrome coronavirus is a deubiquitinating enzyme. J Virol 79, 15199-208 (2005). 30. Shao, Y. M. et al. Structure-Based Design and Synthesis of Highly Potent SARS-CoV 3CL Protease Inhibitors. ChemBioChem 8, 1654-1657 (2007). 31. Wu, C.-Y. et al. Small molecules targeting severe acute respiratory syndrome human coronavirus. Proc Natl Acad Sci U S A 101, 10012-10017 (2004). 32. Lee, C.-C. et al. Structural basis of mercury- and zinc-conjugated complexes as SARS-CoV 3C-like protease inhibitors. FEBS Lett 581, 5454-5458 (2007). 33. Hsu, J.T.A. et al. Evaluation of metal-conjugated compounds as inhibitors of 3CL protease of SARS-CoV. FEBS Lett 574, 116-120 (2004). 34. Shie, J. J. et al. Inhibition of the severe acute respiratory syndrome 3CL protease by peptidomimetic α,β-unsaturated esters. Bioorg Med Chem 13, 5240-5252 (2005). 35. Shie, J. J. et al. Discovery of Potent Anilide Inhibitors against the Severe Acute Respiratory Syndrome 3CL Protease. J Med Chem 48, 4469-4473 (2005). 36. Wu, C. Y. et al. Stable Benzotriazole Esters as Mechanism-Based Inactivators of the Severe Acute Respiratory Syndrome 3CL Protease. Chem Biol 13, 261-268 (2006). 37. Tsai, K. C. et al. Discovery of a Novel Family of SARS-CoV Protease Inhibitors by Virtual Screening and 3D-QSAR Studies. J Med Chem 49, 3485-3495 (2006). 38. Lu, I.L. et al. Structure-Based Drug Design and Structural Biology Study of Novel Nonpeptide Inhibitors of Severe Acute Respiratory Syndrome Coronavirus Main Protease. J Med Chem 49, 5154-5161 (2006). 39. Chen, C.N. et al. Inhibition of SARS-CoV 3C-like Protease Activity by Theaflavin-3,3'-digallate (TF3). Evid Based Complement Alternat Med 2, 209-215 (2005). 40. Wen, C. C. et al. Specific Plant Terpenoids and Lignoids Possess Potent Antiviral Activities against Severe Acute Respiratory Syndrome Coronavirus. J Med Chem 50, 4087-4095 (2007). 41. Shao, Y. M. et al. Design, synthesis, and evaluation of trifluoromethyl ketones as inhibitors of SARS-CoV 3CL protease. Bio Med Chem 16, 4652-4660 (2008). 42. Ramajayam, R. et al. Synthesis, docking studies, and evaluation of pyrimidines as inhibitors of SARS-CoV 3CL protease. Bio Med Chem Lett 20, 3569-3572 (2010). 43. Kuo, C. J. et al. Individual and common inhibitors of coronavirus and picornavirus main proteases. FEBS Lett 583, 549-555 (2009). 44. Ramajayam, R. et al. Synthesis and evaluation of pyrazolone compounds as SARS-coronavirus 3C-like protease inhibitors. Bio Med Chem 18, 7849-7854 (2010). 45. Kuo, C. J. et al. Characterization of SARS main protease and inhibitor assay using a fluorogenic substrate. Biochem Biophy Res Comm 318, 862-867 (2004). Chapter 4 References 1. Shoemaker, B.A. et al. Deciphering protein-protein interactions. Part I. Experimental techniques and databases. PLoS Comput Biol 3, e42 (2007). 2. Sperandio, O. et al. Rationalizing the chemical space of protein-protein interaction inhibitors. Drug Discov Today 15, 220-9 (2010). 3. Wells, J.A. et al. Reaching for high-hanging fruit in drug discovery at protein-protein interfaces. Nature 450, 1001-1009 (2007). 4. Lin, Y.F. et al. Intracellular beta-Tubulin/Chaperonin Containing TCP1-beta Complex Serves as a Novel Chemotherapeutic Target against Drug-Resistant Tumors. Cancer Res 69, 6879-6888 (2009). 5. Lin, Y.-F. et al. Targeting the XIAP/caspase-7 complex selectively kills caspase-3–deficient malignancies. J Clin Invest 123, 3861-3875 (2013). 6. Sullivan, K.F. Structure and utilization of tubulin isotypes. Annu Rev Cell Biol 4, 687-716 (1988). 7. Mandelkow, E. et al. Microtubular structure and tubulin polymerization. Curr Opin Cell Biol 2, 3-9 (1990). 8. Linse, K. et al. The GTP-binding peptide of beta-tubulin. Localization by direct photoaffinity labeling and comparison with nucleotide-binding proteins. J Biol Chem 263, 15205-10 (1988). 9. Sharp, D.J. et al. Microtubule motors in mitosis. Nature 407, 41-47 (2000). 10. Sawin, K.E. et al. Meiosis, mitosis and microtubule motors. BioEssays 15, 399-407 (1993). 11. Lu, Y. et al. An Overview of Tubulin Inhibitors That Interact with the Colchicine Binding Site. Pharm Res 29, 2943-2971 (2012). 12. Lee, K.M. et al. Class III β-tubulin, a marker of resistance to paclitaxel, is overexpressed in pancreatic ductal adenocarcinoma and intraepithelial neoplasia. Histopathology 51, 539-546 (2007). 13. Montgomery, R.B. et al. Expression of oncogenic epidermal growth factor receptor family kinases induces paclitaxel resistance and alters beta-tubulin isotype expression. J Biol Chem 275, 17358-63 (2000). 14. Umezu, T. et al. Taxol resistance among the different histological subtypes of ovarian cancer may be associated with the expression of class III beta-tubulin. Int J Gynecol Pathol 27, 207-212 (2008). 15. Urano, N. et al. Clinical significance of class III beta-tubulin expression and its predictive value for resistance to docetaxel-based chemotherapy in gastric cancer. Int J Oncol 28, 375-81 (2006). 16. Hari, M. et al. Mutations in alpha- and beta-tubulin that stabilize microtubules and confer resistance to Colcemid and vinblastine. Mol Cancer Ther 2, 597-605 (2003). 17. Yin, S.H. et al. Amino acid substitutions at proline 220 of beta-tubulin confer resistance to paclitaxel and colcemid. Mol Cancer Ther 6, 2798-2806 (2007). 18. Llorca, O. et al. Analysis of the Interaction between the Eukaryotic Chaperonin CCT and Its Substrates Actin and Tubulin. J Struct Biol 135, 205-218 (2001). 19. Young, J.C. Analysis of the Interaction between the Eukaryotic Chaperonin CCT and Its Substrates Actin and Tubulin. Pathways of chaperone-mediated protein folding in the cytosol. Nat Rev Mol Cell Biol 5, 781-791 (2004). 20. de Boer, B. et al. Synthesis and Characterization of Conjugated Mono- and Dithiol Oligomers and Characterization of Their Self-Assembled Monolayers. Langmuir 19, 4272-4284 (2003). 21. Feng, F. Analysis of the Interaction between the Eukaryotic Chaperonin CCT and Its Substrates Actin and Tubulin. Anthraquinone-2-sulfonyl chloride: a new versatile derivatization reagent—synthesis mechanism and application for analysis of amines. Talanta 57, 481-490 (2002). 22. D. Mysyk et al.Electron acceptors of the fluorene series. Part 6.1 Synthesis of 4,5-dinitro-9-X-fluorene-2,7-disulfonic acid derivatives, their charge transfer complexes with anthracene and sensitization of photoconductivity of poly-N-(2,3-epoxypropyl)carbazole. J Chem Soc, Perkin Trans 2, 537-546 (1997). 23. Hansch, C. et al. Aromatic substituent constants for structure-activity correlations. J Med Chem 16, 1207-1216 (1973). 24. Taylor, R. Analysis of the Interaction between the Eukaryotic Chaperonin CCT and Its Substrates Actin and Tubulin. Use of Crystallographic Data in Searching for Isosteric Replacements - Composite Crystal-Field Environments of Nitro and Carbonyl Groups. Pestic Sci 29, 197-213 (1990). 25. Meanwell, N.A. Synopsis of Some Recent Tactical Application of Bioisosteres in Drug Design. J Med Chem 54, 2529-2591 (2011). | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/55358 | - |
| dc.description.abstract | 雜環化合物廣泛分佈於自然界，且已成為不可或缺的上市藥物。在本論文中，我分別在第二、三章描述一些雜環化合物的合成及當作抗病毒藥劑來抑制神經胺酸酶及人類嚴重急性呼吸道症候群冠狀病毒(SARS-CoV)蛋白酶的活性，並在第四章描述一些藉破壞β-tubulin: CCT-β來抗癌的藥劑。
流感病毒抗藥性的發生讓新抗病毒藥劑的研究變得必要。在目前的研究我們使用高通量篩選從約6800個化合物找到KR-72039作為H1N1及H5N1神經胺酸酶(NA)的抑制劑。結構－活性研究得到系列中最佳的H5N1 NA抑制劑3e (IC50 = 2.8 μM)，具混合型酵素抑制模式(Kic = 2.9 μM及 Kiu = 5.6 μM)，並能抑制病毒複製 (EC50 = 27 μM)。電腦模擬顯示我們的化合物主要在結合NAs 活性區的loop-430。化合物3l 可同時抑制H7N9和H7N9-R292K NAs。這些化合物的CC50 >200 μM，因此可作為發展新一類抗流感藥物的起始。 雖然2005年後已沒有SARS病例，然而新一類型的冠狀病毒稍後被稱為中東急性呼吸道症候群冠狀病毒 (MERS-CoV) 在2012年初期發生，這是能感染人類的第六個冠狀病毒。雖然許多SARS-Co V蛋白酶的抑制劑已被發現，但尚未有抗冠狀病毒的藥物被研發上市。我們實驗室早先曾報導一些 pyrazole 化合物作為3CL蛋白酶的抑制劑，因此我繼續合成及試驗pyrazolone 類似物，並發現一些抑制劑。電腦模擬預測可能的結合部位可能在蛋白雙體交接位置導致影響雙體形成。最佳抑制劑3q，只需在7.9 μM 即可抑制酵素活性。有趣的是3l可藉結合到相似環境來抑制NAs及SARS蛋白酶的活性。 從我們已發表的論文(Lin et al., Cancer Res. 2009) I-Trp 和β-tubulin的Cys354形成共價性鍵結，因而破壞 β-tubulin: CCT-β複體。藉使用此熱點，陳世勳博士發現了一個可逆型破壞protein-protein interaction (PPI)的抑制劑，因此造成過度表現CCT-β的抗藥性癌細胞死亡。我們也從事SAR來發現必要的pharmacophore。發現在這個hit中 Nitro及其他芳香及疏水性基團對於活性是不能或缺的。 | zh_TW |
| dc.description.abstract | Heterocyclic compounds are widely distributed in nature and has become indispensable component of the marketed drugs. In this thesis, I describe the synthesis and structure-activity relationship (SAR) of some heterocyclic compounds as antiviral agents namely neuraminidase inhibitors, SARS-CoV protease inhibitors in chapter 2 and 3, respectively, and anti-cancer agents by disrupting β-tubulin: CCTβ complexes in chapter 4.
The emergence of resistance among flu viruses has made search for new antiviral agents essential. In the present study, we performed high-throughput screening on ~6800 compounds to identify KR-72039 as an inhibitor of H1N1 and H5N1 neuraminidases (NAs). Structure-activity relationship studies was conducted leading to the best inhibitor 3e which inhibited H5N1 NA (IC50 = 2.8 μM) with binding affinity (Kic = 2.9 μM and Kiu = 5.6 μM) as a mixed-mode inhibitor to block viral replication (EC50 = 27 μM). In silico analysis indicated that our compounds predominantly occupy loop-430 around NA active site. Compound 3l additionally inhibited both H7N9 and H7N9-R292K NAs. The CC50 for these compounds were >200 μM. These inhibitors serve as a starting point for the development of a novel class of antiflu agents. Though there was no case of SARS after 2005, a new class of coronavirus which was later named as Middle East respiratory syndrome coronavirus (MERS-CoV) emerged in early 2012. This is the sixth coronavirus that could infect humans. Although many inhibitors of the SARS-CoV proteases have been discovered, no anti-coronaviral drug has been developed so far. We had earlier reported some pyrazole compounds as the 3CL protease inhibitors, so we continued to synthesize and test the pyrazolone analogs. A few compounds showed inhibitory activity. Docking experiments predicted the probable binding site of these compounds is at the dimer interface to block the active dimer formation. The best compound 3q inhibited the protease at 7.9 μM. Interestingly, 3l inhibited both neuraminidase and SARS protease by binding to the similar environments in both enzymes. From our published results (Lin et al., Cancer Res. 2009) I-Trp forms covalent linkage with Cys354 of β-tubulin, thereby disrupting β-tubulin: CCT-β complexes. Using this as a hot spot, Dr. Shih-Hsun Chen identified a reversible inhibitor for disrupting this protein-protein interaction (PPI) and causing cell death of CCT-β overexpressed cancers, which are multidrug resistant. We performed SAR to identify the essential pharmacophore. Nitro substitution in the hit is indispensable for the activity along with aromatic or hydrophobic side chain. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T03:58:19Z (GMT). No. of bitstreams: 1 ntu-103-D97b46018-1.pdf: 4955622 bytes, checksum: c197aa0e58f1ed7dc6e9a94f4d17c16e (MD5) Previous issue date: 2014 | en |
| dc.description.tableofcontents | Table of Content
口試委員會審定書 ………………………………………………………………………i 誌謝 (Acknowledgement) …………………………………………….ii 中文摘……………………………………………………………........iii Abstract ………………………………………………………..……....iv List of abbreviations …………………………………………………viii 1. Chapter 1 1.1. General Introduction ……………………………………………….1 1.2. Reference …………………………………………………………..4 2. Chapter 2: Identification, synthesis and SAR studies of new neuraminidase inhibitors 2.1. Introduction ………………………………………………………..5 2.2. Results and Discussion …………………………………………...13 2.3. Conclusion ………………………………………………………..21 2.4. Experimental Section 2.4.1. Preparation of substituted furfurals ………………………...21 2.4.2. General procedure for the synthesis of pyrazolones ……….23 2.4.3. Preparation of substituted pyrazolones …………………….23 2.4.4. High-throughput Screening and Determination of IC50 and Ki ……………………………………………………………...23 2.4.5. Determination of CC50 ……………………………………...25 2.4.6. Determination of EC50 against H5N1 virus …………….......25 2.5. Spectral Data ……………………………………………………...26 2.6. Reference …………………………………………………………39 2.7. 3. Chapter 3: Design and synthesis of the inhibitors of SARS-CoV protease 3.1. Introduction ………………………………………………………46 3.2. Results and Discussion …………………………………………...50 3.3. Conclusion ………………………………………………………..54 3.4. Experimental Section 3.4.1. Preparation of pyrazolones analogs ………………………..55 3.4.2. SARS-CoV 3CLPro assay …………………………………...55 3.5. Spectral Data ……………………………………………………56 3.6. Reference …………………………………………………………58 4. Chapter 4: SAR studies of the β-tubulin: CCT-β disruptor 4.1. Introduction ………………………………………………………62 4.2. Disrupting PPI of β-tubulin: Chaperonin containing TCP1 (CCT)β ……………………………………………………………64 4.3. Results and Discussion 4.3.1. Synthesis ……………………………………………………66 4.3.2. SAR studies ………………………………………………...67 4.4. Conclusion ………………………………………………………..71 4.5. Experimental Section ……………………………………………..72 4.6. Spectral Data ……………………………………………………...74 4.7. Reference …………………………………………………………78 5. Chapter 5 5.1. Conclusion ………………………………………………………..81 5.2. Reference …………………………………………………………84 6. List of publications…………………………………………………..85 7. Appendices…………………………………………………………....86 | |
| dc.language.iso | en | |
| dc.title | 合成及評估不同雜環化合物作為抗病毒及抗癌藥劑 | zh_TW |
| dc.title | Synthesis and Evaluation of Various Heterocyclic
Compounds as Antiviral and Anticancer Agents | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 103-1 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 方俊民(Jim-Min Fang),陳昭岑(Chao-Tsen Chen),羅禮強(Lee-Chiang Lo),吳世雄(Shih-Hsiung Wu),陳基旺(Ji-Wang Chern) | |
| dc.subject.keyword | Neuraminidase,SARS Co-V,β-Tubulin, | zh_TW |
| dc.relation.page | 0 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2014-11-30 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 生化科學研究所 | zh_TW |
| 顯示於系所單位： | 生化科學研究所 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-103-1.pdf 目前未授權公開取用 | 4.84 MB | Adobe PDF |
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