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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/24018完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳基旺 | |
| dc.contributor.author | RAHUL SUBHASH TALEKAR | en |
| dc.contributor.author | 塔立卡 | zh_TW |
| dc.date.accessioned | 2021-06-08T05:14:13Z | - |
| dc.date.copyright | 2006-09-18 | |
| dc.date.issued | 2006 | |
| dc.date.submitted | 2006-07-07 | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/24018 | - |
| dc.description.abstract | The aim of this dissertation is to design, synthesis and biological evaluation of quinoline analogues of medicinal interest. Quinoline or 8-quinolinol heterocycles are considered as ideal leads for further optimization in search for novel compounds of medicinal interest. In Chapter 1, we developed novel 8-quinolinols, 8-methoxyquinolines substituted at C2 position with long carbon chain (C9-C13) alcohols, long chain alkyl bromides or long chain fatty acetates. In this study, we designed a skeleton, which might serve as Zn++ metal ions chelator and nerve growth stimulator. It is interesting to note that, these compounds are free of cytotoxicity, making them as ideal candidate for AD. In addition, several compounds demonstrated intense fluorescence under UV light. Therefore, they might serve as efficient candidate for studying the activity in living cells. In Chapter 2, series of antitumor quinoline analogues (nonhalogenated 10-15 and halogenated 18-80 styrylquinolines) and halogenated amide quinolines 91-96 were prepared. Many styryl analogues demonstrated potent antitumor activity with GI50 in the submicromolar range against HepG2 tumor cells. The best compounds 2-[2-(4-Acetyl-oxyphenyl)vinyl]-5-chloro-7-iodo-8-methoxyquinoline (50), 2-[2-(4-Hydroxyphenyl)vinyl]-5-chloro-7-iodo-8-met-hoxyquinoline (67) in this series showed GI50 of 20 nM and caused S-phase arrest. The detail SAR study showed that presence of 8-hydroxy or 8-acetoxy group and polar substituents on styryl phenyl ring are required for potent anticancer activity. Replacement of styryl bond with amide or substitution of 8-methoxy group results in loss of anticancer potency. In Chapter 3, we describe nonreductive method of selective deiodination. In the presence of tertiary amine and catalytic amount of water several iodinated compounds underwent deiodination of ortho-iodo group. The prominent future of this reaction that it selectively removes ortho-iodo group without any effect on para-iodo group and other halogens. Absence of reducing agent and short reaction times are the additional future of this reaction. In Chapter 4, we report novel styrylquinolines as novel candidate for small molecule based organic light emitting diodes (SMOLED). Compounds DCSQM and DCSQA based on donor-conjugated-acceptor architecture (D-π-A) showed different emission pattern in solvents of varying polarity. Both compounds exhibited excellent thermal and electrochemical properties. Device fabricated using DCSQM showed blue emission thus making itself as ideal candidate for OLED device. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-08T05:14:13Z (GMT). No. of bitstreams: 1 ntu-95-D90423003-1.pdf: 5188807 bytes, checksum: f5f0b71da873d211d9b111cb43cab192 (MD5) Previous issue date: 2006 | en |
| dc.description.tableofcontents | Dedication......................................................................................................................I
Acknowledgements………………………………………………………………….II Table of Contents…………………………………...………………………………III List of Figures………………………………………………………………………IV List of Tables………………………………………………………………….........VI List of Schemes………………………………………………………………….VII Abstract………………………………………………………………………………1 Introduction…………………………………………………………………………..2 Chapter 1. Design, Synthesis and Effects of Quinoline Substituted Long Chain Fatty Alcohols on Neurite Outgrowth for the Treatment of Alzheimer’s Disease…………………..12 Introduction……………………………………………………………………13 Result and discussion………………………………………………….………20 Summary…………………………………………………………………….33 Experimental…………………………………………………………………..34 References……………………………………………………………………..47 2. Design and Synthesis of Quinoline Derivatives as Potent Anticancer Agents…….50 Introduction…………………………………………………………………...51 Result and discussion………………………………………..………………...58 Biological activity……………………………………………………………73 Summary…………………………………………………………………101 Experimental…………………………………………………………………100 References……………………………………………………………………141 3. Nonreductive Deiodination of ortho-Iodophenols Using Tertiary Amines……….146 Introduction………………………………………………………………...147 Result and discussion………………………………………………………...148 Summary…………………………………………………………………152 Experimental………………………………………………………………153 References……………………………………………………………………158 4. Design, Synthesis, and Electrochemical Properties of 8-Substituted 5,7-Dichloro-2- Styrylquinolines as Potential Light Emitters……………………………………..160 Introduction…………………………………………………………………161 Result and discussion……………………………………………………...…162 Summary………………………………………………………………….179 Experimental……………………………………………………………….180 References………………………………………………………………….183 Conclusion……………………………………………………………………………18 List of Figures Figure 1-1. Research phases toward realizing therapeutics for neurological disease……13 Figure 1-2. Proteolytic processing of the amyloid precursor protein (APP)……………15 Figure 1-3. Zinc induced accumulation of Aβ results in nerve damage…………………16 Figure 1-4. Chemical structure of Clioquinol……………………………………………17 Figure 1-5. Chemical structure of neurotrophic long chain fatty alcohols………………19 Figure 1-6. Retrosynthesis of designed compound………………………………………20 Figure 1-7. Modified retrosynthesis of designed compound…………………………….28 Figure 2-1. The mammalian cell cycle…………………………………………………..52 Figure 2-2. A schematic overview of some essential steps in cell cycle regulation……54 Figure 2-3. Structure of resveratrol, trans-retinobenzoic acid, trans-combretastatin…...56 Figure 2-4. Structure of 2-Styrylquinazolin-4(3H)-one and its derivatives……………57 Figure 2-5. Structure of camptothecin, elipticine, podophyllotoxin analogues…………57 Figure 2-6. Design of heterocycle-conjugated styrene derivatives as anticancer agents. 58 Figure 2-7. Design of novel styrene quinoline derivatives as anticancer agents………58 Figure 2-8. Design of halogenated styrene quinoline derivatives as anticancer agents.61 Figure 2-9. Design of halogenated amide quinoline derivatives as anticancer agents...70 Figure 2-10. Flow cytometric analysis of HepG2 cells treated with 2 and 6 ………...….85 Figure 2-11. Effect of compound 2 and 6 on HepG2 cell cycle progression…………..86 Figure 2-12. Flow cytometric analysis of HepG2 cells treated with 3 and 7 ……………86 Figure 2-13. Effect of compound 3 and 7 on HepG2 cell cycle progression…………….87 Figure 2-14. Flow cytometric analysis of HepG2 cells treated with 3 and 7 …………....87 Figure 2-15. Flow cytometric analysis of AGS cells treated with 3 and 7 ………….…..88 Figure 2-16. Flow cytometric analysis of A-549 cells treated with 3 and 7 ………….....88 Figure 2-17. Flow cytometric analysis of HepG2 cells treated with 49 and 67 ………....89 Figure 2-18. Flow cytometric analysis of Hep2 cells treated with 74 and 75 ………......90 Figure 2-19. Flow cytometric analysis of AGS cells treated with 74 and 75 ………...…91 Figure 2-20. Flow cytometric analysis of A-549 cells treated with 74 and 75 ……….....91 Figure 2-21. Flow cytometric analysis of A-549 cells treated with 74 and 75 ……….…92 Figure 2-22. Flow cytometric analysis of HT-29 cells treated with 74 and 75 ………….93 Figure 2-23. Flow Cytometric analysis of HepG2 cells treated with 98 ………….…….93 Figure 2-24. Fluorescence microscopy images showing appearance of HepG2 cells following drug treatment for 16 h.………………………………………….94 Figure 2-25. Western blot study ………...……………………………………………….95 Figure 4-1. Absorption and normalized solution photoluminescence (PL) spectra for 2, 3, DCSQM, and DCSQA in CHCl3…………………………………….165 Figure 4-2a. Absorption spectra for 2 x 10-5 M of DCSQM in different solvents……...166 Figure 4-2b. Absorption spectra for 2 x 10-5 M of DCSQA in different solvents………166 Figure 4-2c. Normalized photoluminescence spectra for 2 x 10-5 M of DCSQM and DCSQA in different solvents……………………………………………...167 Figure 4-3. Absorption spectra for 2 x 10-5 M of DCSQM in different solvents……....178 Figure 4-4. Emission of DCSQM and DCSQA in solvents of varying polarity at wavelength………………………………………………………………....168 Figure 4-5. Single X-ray crystal structure of DSQA…………………………………...170 Figure 4-6. Molecular packing diagram of DCSQA showing extensive π-π interactions……............................................................................................170 Figure 4-7. The optimized structures of DCSQM (4a) and DCSQA (5a) at the B3LYP/6-31G* level…….............................................................................................174 Figure 4-8. The HOMO and LUMO for DCSQM and DCSQA………………………..175 Figure 4-9. Comparison of reduction cyclic voltammograms of DCSQM (red) and DCSQA (blue)…….......................................................................................177 Figure 4-10. Electroluminescence spectrum of a film of DCSQM…………………….178 Figure 4-11. Current density-voltage-luminescence characteristics of an EL device using DCSQM……............................................................................178 List of Tables Table 2-1. Cyclin-CDK complexes are activated at specific points of the cell cycle. CAK, CDK activating kinase…………………………….……………53 Table 2-2. Cytotoxic activity of styrylquinolines (2-15)………………………………..75 Table 2-3. Cytotoxic activity of styrylquinolines (18-26)………………………………76 Table 2-4. Cytotoxic activity of styrylquinolines (27-33)………………………………77 Table 2-5. Cytotoxic activity of styrylquinolines (35-42)………………………………78 Table 2-6. Cytotoxic activity of styrylquinolines (45-65)………………………………79 Table 2-7. Cytotoxic activity of styrylquinolines (66-72)………………………………80 Table 2-8. Cytotoxic activity of styrylquinolines (73-75)………………………………81 Table 2-9. Cytotoxic activity of styrylquinolines (78-87)………………………………82 Table 2-10. Cytotoxic activity of styrylquinolines (91-100)……………………………83 Table 3-1. Deiodination of o-iodo-hydroxylated arenes in the presence of tertiary amines……………………………….………………………………151 Table 4-1. Absorption and Emission for DCSQM and DCSQA in Different Solvents..165 Table 4-2. Crystal Data and Structure Refinements for DCSQA………………………171 Table 4-3. Bond lengths (Å) and angles (o) for DCSQA……………………………….172 Table 4-4. Estimated Experimental and Theoretical HOMO and LUMO Energy Levels…………………………………………………………...173 Table 4-5. Photophysical, Thermal, and Electrochemical Properties of DCSQM and DCSQA…………………………………………………………………175 List of Schemes Scheme 1-1...................................................................................................................21 Scheme 1-2. .................................................................................................................22 Scheme 1-3. .................................................................................................................23 Scheme 1-4. .................................................................................................................24 Scheme 1-5. .................................................................................. ... ... ......................25 Scheme 1-6. ..............................................................................................................25 Scheme 1-7. ................................................................................................................26 Scheme 1-8. ................................................................. ... ... .......................................27 Scheme 1-9. .................................................................................................................28 Scheme 1-10. ...............................................................................................................29 Scheme 1-11. ...............................................................................................................29 Scheme 1-12. ............................................................................................................30 Scheme 1-13. ...............................................................................................................30 Scheme 1-14. ..............................................................................................................31 Scheme 1-15. ..............................................................................................................32 Scheme 2-1................................................................................................................59 Scheme 2-2...................................................................................................................59 Scheme2-3................................................................................................................60 Scheme 2-4.................................................................................................................60 Scheme 2-5................................................................................................................62 Scheme 2-6.................................................................................................................63 Scheme 2-7...................................................................................................................64 Scheme 2-8...............................................................................................................65 Scheme 2-9................................................................................................................66 Scheme 2-10..........................................................................................................67 Scheme 2-11...........................................................................................................68 Scheme 2-12..............................................................................................................68 Scheme 2-13.......................................................................................................69 Scheme 2-14............................................................................................................71 Scheme 2-15..........................................................................................................71 Scheme 2-16...........................................................................................................72 Scheme 2-17......................................................................................................72 Scheme 3-1………………………………………………………………………..146 Scheme 3-2……………………………………………………………………..147 Scheme 3-3……………………………………………………………………..150 Scheme 3-4……………………………………………………………………..150 Scheme 4-1…………………………………………………………………….163 | |
| dc.language.iso | en | |
| dc.subject | 奎寧 | zh_TW |
| dc.subject | Quinoline | en |
| dc.title | Quinoline 衍生物之設計、合成與生物活性評估 | zh_TW |
| dc.title | Design,Synthesis and Biological Evaluation of Quinoline Analogues | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 94-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 王光昭,李安榮,曾誠齊,忻凌偉,陳香惠,孔繁璐,顧記華 | |
| dc.subject.keyword | 奎寧, | zh_TW |
| dc.subject.keyword | Quinoline, | en |
| dc.relation.page | 193 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2006-07-10 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 藥學研究所 | zh_TW |
| 顯示於系所單位： | 藥學系 | |
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