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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 方俊民(Jim-Min Fang) | |
| dc.contributor.author | Nai-Wei Chen | en |
| dc.contributor.author | 陳乃維 | zh_TW |
| dc.date.accessioned | 2021-06-16T05:47:07Z | - |
| dc.date.available | 2024-12-31 | |
| dc.date.copyright | 2014-09-04 | |
| dc.date.issued | 2014 | |
| dc.date.submitted | 2014-08-11 | |
| dc.identifier.citation | 1. Grozinger, C. M.; Schreiber, S. L. Chem. Biol. 2002, 9, 3–16. Deactylase enzymes: biological functions and the use of small-molecule inhibitors.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/56766 | - |
| dc.description.abstract | 組蛋白去乙醯酶 (HDACs) 會將組蛋白上氮端 (N-) 的離胺酸基團進行去乙醯化反應，藉此影響多種生物機制，在癌症及神經退化疾病的致病機制上都扮演重要的角色。在膽固醇的生合成路徑中，3-羥基-3-甲基戊二酸輔酶A還原酶 (HMGR) 為合成甲羥戊酸的速率決定酵素。市面上他汀類 (statins) 之藥物為 3-羥基-3-甲基戊二酸輔酶A還原酶的抑制劑，普遍用來治療高血酯。現今研究指出，組蛋白去乙醯酶及3-羥基-3-甲基戊二酸輔酶A還原酶之抑制劑為有發展潛力的新型抗癌藥物。
根據里賓斯基五規則 (Lipinski’s “Rule of Five”) 及設計多重功能配體(designed multiple ligands, DMLs) 概念中的接合 (fusing) 策略，我們首先設計且合成了樂瓦斯他汀–羥胺作為有效且低細胞毒性的組蛋白去乙醯酶和3-羥基-3-甲基戊二酸輔酶A還原酶的雙重抑制劑。羥胺 (hydroxylamine) 在組蛋白去乙醯酶抑制中扮演鋅離子配位官能基團 (zinc-binding group)，且取代他汀類藥物中的羧酸官能基，達到抑制3-羥基-3-甲基戊二酸輔酶A還原酶的效果。然而，羥胺基團的藥物動力學 (pharmacokinetics) 特性差且水解後會對生體產生慢性毒性。因此，我們在本篇研究中首先藉由肽鍵耦合反應或親核反應在樂瓦斯他汀上修飾一系列不同鋅離子配位官能基，期望能改善樂瓦斯他汀–羥胺的藥物動力學特性和提升雙重酵素抑制活性。同時我們也合成了親水性較高的氟伐他汀鈉–羥胺(fluvastatin–hydroxamate) 之衍生物。根據離體檢測結果 (enzymatic and cell-based assay)，化合物 28, 32及 34 表現出比其他衍生物高的組蛋白去乙醯酶之抑制活性，因此我們認為強的鋅離子配位官能基團須有自由的末端羥基，且其大小和剛性都會影響抑制活性。氟伐他汀鈉–羥胺擁有跟樂瓦斯他汀–羥胺相當的雙重抑制活性，但其離體細胞檢測 (cell-based assay) 顯示氟伐他汀鈉的高親水性可能減弱了氟伐他汀鈉–羥胺的細胞穿透度 (cell permeability)。總結以上研究，羥胺仍然是目前設計此雙重抑制劑中最適合的鋅離子配位官能基團。 另一方面，過渡金屬經常和多種抑制劑或細胞毒素形成前驅藥物 (prodrug)，在特定的生理環境中被活化而釋放出活性物質，藉此毒殺特定細胞。因此，我們利用不同過渡金屬合成一系列樂瓦斯他汀–羥胺之過渡金屬錯合物，嘗試改善羥胺之藥物動力學特性也建構樂瓦斯他汀–羥胺的控釋效果，提高針對毒殺腫瘤細胞之選擇性。銅二價的錯合物 42 和 43對組蛋白去乙醯酶 6 有比樂瓦斯他汀–羥胺更高的抑制活性。在缺氧及含氧的離體細胞檢測中，銅二價的錯合物 42 和 43表現跟樂瓦斯他汀–羥胺相當且優於鐵三價的錯合物41的酵素抑制活性。在缺氧環境中，鈷三價及釓三價的錯合物49及51比在含氧環境中對組蛋白去乙醯酶 3的抑制活性高了20–40%。在離體細胞檢測中發現銅二價的錯合物 42 和 43加入維他命C作為溫和還原劑後，在特定條件中能促進配體的釋放而提升抑制活性。加入維他命C的酵素和離體細胞檢測皆會繼續進行。紫外光–可見光吸收光譜 (UV–Vis spectra) 可推測此金屬前驅藥物可在缺氧及酸性環境下被活化而釋放出活性物質樂瓦斯他汀–羥胺。在初步的體內異體移植腫瘤檢測 (xenograft model) 中，鐵三價之錯合物 41 能有效的抑制人結直腸癌細胞的生長。在未來也會增加異體移植腫瘤檢測的樣品數。之後也會進行這些金屬錯合物之細胞毒性檢測。在未來我們也將設計利用釓三價的錯合物 51 做為核磁共振成像 (MRI) 的對比劑以觀測樂瓦斯他汀–羥胺在體內的藥物分佈情況。 | zh_TW |
| dc.description.abstract | Histone deacetylases (HDACs) cause deacetylation of the lysine groups on the histone, and play an important role in several diseases including cancer and neurodegenerative disease. 3-Hydroxy-3-methylgluraryl coenzyme A reductase (HMGR) is the rate-controlling enzyme for conversion of HMG-CoA to mevalonic acid in biosynthetic pathway of cholesterol. Statins are a class of HMGR inhibitors used as anti-hypercholesterolemia agents. Nowadays, HDACs and HMGR inhibitors have emerged as potential anti-cancer agents. Based on Lipinski’s “Rule of Five” and fused strategy, we have previously designed and synthesized lovastatin–hydroxamate (LOVA–HA) as the dual-action inhibitor targeting HDACs and HMGR with IC50 values in nanomolar range, but low cytotoxicity to normal cells. The hydroxamate group acts as a zinc binding group (ZBG) for HDACs inhibition and as a surrogate of carboxylic acid in statins. However, the hydroxamate group may have poor pharmacokinetic properties and chronic toxicity after hydrolysis. Therefore, we performed structural modification on LOVA–HA (22) by introducing different ZBGs via amide bond formation with lovastatin (19, in carboxylate form) or direct nucleophilic attack on activated statins in lactone form including lovastatin (11) and fluvastatin (37) to improve pharmacokinetic properties and inhibitory activities for cancer treatment. Based on the in vitro assays, 28, 32 and 34 having terminal N-methylhydroxamic, picolylamine and 2-hydroxycyclohexylamide moieties showed less inhibition than LOVA–HA, indicating that free terminal hydroxyl group, size and rigidity of ZBGs play vital roles in HDAC inhibitory activities. Fluvastatin–hydroxamate (38) showed comparable inhibition against HDAC enzymes but poorer inhibition in HCT116 cells than 22, presumably due to higher hydrophilicity of fluvastatin. Hydroxamate may be still the most suitable and stronger ZBG in dual-action inhibitors so far.
Transition metals are often used as chaperones to inhibitors and cytotoxins to form prodrugs which will be activated in specific physiological environments to selectively kill specific cells. Therefore, we synthesized LOVA–HA metallo-complexes in attempts to improve pharmacokinetic properties and construct the controlled-release function. LOVA–HA Cu(II)-complex (a mixture of 42/43) showed a better inhibitory activity against HDAC6 than LOVA–HA. Under either normoxia or hypoxia conditions, LOVA–HA Cu(II)-complex (42/43) had comparable inhibitory activity to LOVA–HA and superior to 41. LOVA–HA Co(III)- and Gd(III)-complexes 49 and 51 showed 20–40% of enhancement in HDAC3 inhibition in hypoxia conditions. The prodrug is activated in hypoxia and acidic environment according to in vitro assays and UV–vis spectra. Based on the preliminary results of the cell-based assays of Cu(II)-complex 42/43, the presence of (L)-ascorbic acid as a mild reducing agent would facilitate the ligand releasing in specific conditions. The enzymatic and cell-based assays of other LOVA–HA metallo-complexes with ascorbic acid are undergoing. 41 had effect on suppressing the tumor growth in a preliminary xenograft model and will repeat this experiment with more mice in a due course. Whether the metallo-complexes are toxic will be determined in a due course. [Gd(LOVA–HA)3]•3H2O (51) may be utilized as a contrast agent in MRI to study the distribution of LOVA–HA in body. | en |
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| dc.description.tableofcontents | Table of Contents
謝誌 ..................................................... I Abstract in Chinese ..................................................................................................... IV Abstract in English .................................................................................................... VII Table of Contents .......................................................................................................... X Index of Figures ........................................................................................................ XIV Index of Schemes .................................................................................................... XXII Index of Equations ................................................................................................ XXIII Index of Tables ....................................................................................................... XXIV Abbreviations ......................................................................................................... XXVI Chapter 1. Introduction ................................................................................................ 1 1.1 Histone Deacetylases (HDACs) .................................................................... 1 1.2 Mechanisms for Regulating HDAC Activity ............................................... 5 1.3 Molecular Biology of HDACs ....................................................................... 8 1.3.1 Mechanisms in Chromatin Modification and Remodeling ...................... 8 1.3.2 HDACs Regulate Non-Histone-Correlated Biological Functions .......... 11 1.3.3 Functions of HDACs and Its Inhibitors for Cancer Treatment ............. 14 1.4 Classification and Structures of HDAC Inhibitors .................................. 17 1.5 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase (HMGR) ............. 20 1.6 HMGR Inhibitors and Their Potential Activity for Cancer Treatment ................................................................................................................. 24 1.7 Solid Tumors ................................................................................................ 28 1.8 Strategies for Design of Cancer Drugs ...................................................... 29 Chapter 2. Results and Discussion ............................................................................. 33 2.1 Design, Synthesis and Activity Evaluation of Dual-functional Inhibitors with Various Zinc Binding Groups (ZBGs) .......................................................... 33 2.2 Conclusion for Dual-functional Inhibitors with Various Zinc Binding Groups ...................................................................................................................... 53 2.3 Synthesis, Characterization and Activity Evaluation of LOVA–HA Metallo-Complexes ................................................................................................. 56 2.4 Conclusion for LOVA–HA Metallo-Complexes ........................................ 76 Chapter 3. Experimental Section ............................................................................... 80 3.1 General Part ................................................................................................. 80 3.2 Determination of Purity of Compounds ................................................... 82 3.3 Bioassays ....................................................................................................... 82 3.3.1 HDAC Activity Assay ................................................................................ 82 3.3.2 HMG-CoA Reductase Activity Assay ....................................................... 83 3.3.3 Treatment of Metallo-Complexes with (L)-Ascorbic Acid ...................... 83 3.3.4 Cell Culture ................................................................................................ 83 3.3.5 Western Blot Analysis for Determination of HDAC Inhibition ............. 84 3.3.6 Mice Xenograft Model ............................................................................... 84 3.4 Spectrophotometric Studies ........................................................................ 85 3.5 Electrochemistry .......................................................................................... 85 3.6 Synthetic Procedures and Characterization of Compounds ................... 87 References ................................................................................................................... 115 Appendices HPLC, 1H, 13C and 19F NMR Spectra ................................................. 137 Supporting Information ............................................................................................ 157 1. Stability Study of LOVA–HA ............................................................................ 157 2. The Docking Models .......................................................................................... 162 3. ESI−MS and MALDI−TOF MS Analysis of Metallo-Complexes .................. 165 4. HDACs Inhibition Studies by Cell-Based Assays ............................................ 171 5. Cyclic Voltammetry (CV) Study ........................................................................ 175 6. Effect of Metallo-Complexes in a Xenograft Model of Colorectal Cancer .... 176 Index of Figures Figure 1.HDAC-associated proteins and co-repressor complexes ............................ 6 Figure 2. Chromatin modification and remodeling. (a) Histone deacetylation by HDACs and methylation causing chromatin condensation. (b) Histone acetylation by HATs and demethylation reactivate DNA transcription. Ac: acetyl group; Me: methyl group; P: phosphate group; MECP2: methyl-CpG-binding protein ..................................................................... 10 Figure 3. Non-histone-correlated biological functions regulated by acetylation ...... 11 Figure 4. The regulation pathway of tumor cell proliferation by HDAC inhibitors .................................................................................................... 17 Figure 5. Classification and structures of HDAC inhibitors (HDACIs) ................... 18 Figure 6. Structure of SAHA (1) ............................................................................... 19 Figure 7. Mevalonate-associated biosynthetic pathway and regulating functions .... 22 Figure 8. Conversion of HMG-CoA to mevalonate by NADPH reduction .............. 24 Figure 9. (a) Classification of type I & type II statins. (b) General structures of type I (e.g. lovastatin, 11) & type II (e.g. rosuvastatin, 17) statins ..................... 27 Figure 10. Activation of metal chaperon prodrugs, exemplified by cobalt(III)/(II) reduction .................................................................................................... 30 Figure 11. Knowledge-based approach for DMLs. The blue color and green color stands for two separate active components ............................................... 32 Figure 12. Possible docking models of TSA and LOVA with HDAC2.90 (a) The major binding mode of LOVA (yellow) resided into another pocket adjacent to the general active site of HDAC2. Magenta sphere, zinc atom; cyan, mapped TSA. (b) The other binding mode is similar to TSA which bound into the general active site of HDAC2. Magenta sphere, zinc atom; cyan, mapped TSA .............................................................................................. 34 Figure 13. (a) The conjugated LOVA–SAHA derivatives in fusing strategy. (b) The conjugated LOVA–SAHA derivatives in merging strategy. (c) LOVA–SAHA hybrid derivatives. Blue, the HMG-like moiety; red, the hydroxamic acid ........................................................................................ 36 Figure 14. Three possible metabolites of vorinostat (SAHA, 1) ................................ 37 Figure 15. The structure of Zinquin (30) and its chelation to zinc in tridentate fashion ....................................................................................................... 44 Figure 16. The structure of LLX (36) and the docking model of LLX and HDAC2 ...................................................................................................... 51 Figure 17. The general structures of LIX 1104 (39) and desferrioxamine B (40) ...... 56 Figure 18. Structures of vitamin B12 (45), marimastat (46), DCD (47) and PR-104 (48) ............................................................................................................ 63 Figure 19. The structure of [Gd(DTPA)]2− (50) which is an MRI contrast agent ...... 65 Figure 20. UV–vis spectra: (a) [Fe(LOVA–HA)3]•2H2O (41) in THF at different pH values. (b) LOVA–HA (22) in THF at acidic pH 0.4 and 3.9 (λmax = 249 nm). (c) 2.9 × 10−5 M FeCl3•6H2O in THF at pH 0.65 (λmax = 339 nm). (d) 41 was added with different portions of water .......................................... 74 Figure 21. The UV–vis spectra. (a) LOVA–HA Cu(II)-complex (a mixture of 42/43) in THF at different pH values. (b) 3.5 × 10−4 M CuCl2•2H2O in THF pH 0.1 and 2.4 (λmax = 302 nm). (c) A mixture of 42/43 was added with different portions of water ........................................................................................ 75 Figure S1. Hydrolysis of LOVA–HA 22 at pH = 7.4 monitored by HPLC. (a) Co-injection of compound 19 in carboxylate form, peaks B (tR = 16.1 & 18.5 min), and LOVA–HA 22, Peak A (tR = 14.0 min). (b) HPLC analysis at different intervals ................................................................................. 158 Figure S2. Hydrolysis of compound 22 at pH = 4.5 monitored by HPLC. (a) LOVA in carboxylate form (19), peaks B (tR = 17.8 & 20.4 min) (b) Co-injection of compound 19 and LOVA–HA 22, peak A (tR = 15.2 min). (b) HPLC analysis at different intervals ................................................................... 159 Figure S3. Hydrolysis of LOVA–HA 22 at pH = 1.2 monitored by HPLC. (a) Co-injection of compound 19 in carboxylate form, peaks B (tR = 16.1 & 18.5 min), and LOVA–HA 22, Peak A (tR = 14.0 min). (b) HPLC analysis at different intervals ................................................................................. 160 Figure S4. Predicted docking models of compounds 27 and 28 in homology-modeled HDAC1 .................................................................................................... 162 Figure S5. Predicted docking models of compounds in human HDAC2 ................. 163 Figure S6. ESI–MS analysis of [Fe(LOVA–HA)3]•2H2O (41). (a) ESI–MS spectrum of 41, found: m/z 1365.7535 [M + H]+. (b) The calculated ESI–MS spectrum of 41, calcd m/z 1365.7520 [M + H]+. (c) The MS pattern of 41. (d) The calculated MS pattern of 41 ........................................................ 165 Figure S7. ESI–MS analysis of the mixture of Cu(II)-complex [Cu(LOVA–HA)(OCH3)] (42) and [Cu(LOVA–HA)2] (43) obtained by method A. (a) ESI–MS spectrum of Cu(II)-complex. (b) The calculated ESI–MS spectrum of 43, calcd m/z 936.4767 [M + H]+. (c) The calculated ESI–MS spectrum of 42, calcd m/z 499.1990 [M – OCH3]+. (d) The MS pattern of 43, found: m/z 936.4764 [M + H]+. (e) The calculated MS pattern of 43. (f) The MS pattern of 42, found: m/z 499.1984 [M – OCH3]+. (g) The calculated MS pattern of 42 ..................................................................... 166 Figure S8. ESI–MS analysis of the mixture of Cu(II)-complex [Cu(LOVA–HA)(OCH3)] (42) and [Cu(LOVA–HA)2] (43) obtained by method B. (a) ESI–MS spectrum of Cu(II)-complex. (b) The calculated ESI–MS spectrum of 43, calcd m/z 936.4767 [M + H]+. (c) ESI–MS spectrum of Cu(II)-complex. (d) The calculated ESI–MS spectrum of 42, calcd m/z 499.1990 [M – OCH3]+. (e) The MS pattern of 43, found: m/z 936.4776 [M + H]+. (f) The calculated MS pattern of 43. (g) The MS pattern of 42, found: m/z 499.1986 [M – OCH3]+. (h) The calculated MS pattern of 42 ............................................................................................. 168 Figure S9. ESI–MS analysis of [Zn(LOVA–HA)2]•H2O (44). (a) ESI–MS spectrum of 44, found: m/z 937.4753 [M + H]+. (b) The calculated ESI–MS spectrum of 44, calcd m/z 937.4762 [M + H]+. (c) The MS pattern of 44. (d) The calculated MS pattern of 44 ..................................................................... 169 Figure S10. MALDI–TOF MS analysis of [Co(LOVA–HA)3]•(CH3CN)(H2O) (49). Calculated m/z 1427.787 [M + H]+, found: m/z 1427.799 [M + H]+ ....... 170 Figure S11. ESI–MS analysis of [Gd(LOVA–HA)3]•3H2O (51). (a) ESI–MS spectrum of 51, found: m/z 1467.7449 [M + H]+. (b) The calculated ESI–MS spectrum of 51, calcd m/z 1467.7411 [M + H]+. (c) The MS pattern of 51. (d) The calculated MS pattern of 51 ........................................................ 170 Figure S12. Western blot experiments for evaluating the effect of dual-functional inhibitors with various zinc binding groups in HCT116 cell line ........... 171 Figure S13. Western blot experiments for evaluating the effect of metallo-complexes, Cu(II)-complex (42/43) and [Fe(LOVA–HA)3]•2H2O (41) in normoxia and hypoxia HCT116 cell line. Blue letters, relative quantification of amounts of acetylation compared to basal ............................................................. 172 Figure S14. Western blot experiments for evaluating the effect of metallo-complexes, [Zn(LOVA–HA)2]•H2O (44), [Gd(LOVA–HA)3]•3H2O (51) and [Co(LOVA–HA)3]•(CH3CN)(H2O) (49) in normoxia and hypoxia HCT116 cell line. Blue letters, relative quantification of amounts of acetylation compared to basal .................................................................................... 173 Figure S15. Western blot experiments for evaluating the effect of metallo-complex, Cu(II)-complex (42/43) with/without ascorbic acid in normoxia and hypoxia HCT116 cell line. Blue letters, relative quantification of amounts of acetylation compared to basal ............................................................. 174 Figure S16. (a) The cathodic peak potential of Fe(III)-complex 41 measured by cyclic voltammetry (CV) in anhydrous NMP (1.0 mM). All potential were recorded versus Ag/AgCl (saturated) as a reference electrode. (b) The maximum of cathodic potentials of different amount (mmol) of Fe(III)-complex 41................................................................................... 175 Figure S17. Tumor volume after treatment with LOVA–HA Fe(III)-complex 41 or soybean oil (vehicle) in several intervals. Tumor volume was calculated = (tumor volume in different intervals/initial tumor volume). p = 0.18 ......176 Index of Schemes Scheme 1. Preparation of LOVA–amide 26 and LOVA–hydrazide 27. ..................... 39 Scheme 2. Synthesis of N-methyl (28) and O-methyl (29) hydroxylamide derivatives .................................................................................................. 41 Scheme 3. Synthesis of LOVA derivatives with pyridyl groups ................................ 45 Scheme 4. Preparation of benzamide (33), (1R,2S)-hydroxycyclohexylamide (34) and ethanolamide (35) derivatives of lovastatin ............................................... 49 Scheme 5. Preparation of fluvastatin–lactone (37) and fluvastatin–hydroxamate (38) ............................................................................................................ 52 Scheme 6. Synthesis of metallo-complexes [Fe(LOVA–HA)3]•2H2O (41), [Cu(LOVA–HA)(OCH3)] (42) and [Cu(LOVA–HA)2] (43) .................... 60 Scheme 7. Synthesis of [Co(LOVA–HA)3]•(CH3CN)(H2O) (49) and [Gd(LOVA–HA)3]•3H2O (51) ................................................................... 66 Index of Equations Equation 1. Synthesis of bioligand LOVA–HA (22) .................................................... 59 Equation 2. Synthesis of [Zn(LOVA–HA)2]•H2O (44) ................................................ 62 Index of Tables Table 1. Classification of histone deacetylases ......................................................... 3 Table 2. Inhibitory activities of 26–29 against HMGR and HDACs ...................... 42 Table 3. Inhibitory activities of 31 and 32 against HMGR and HDACs ................. 47 Table 4. Inhibitory activities of 33, 34 and 35 against HMGR and HDACs ........... 49 Table 5. Inhibitory activities of 38 against HMGR and HDACs ............................ 53 Table 6. The IC50 values of metallo–(LOVA–HA) complexes against HMGR and HDACs determined by enzymatic assays .................................................. 68 Table S1. Remaining LOVA–HA (22) at different acidity and intervals as quantified by HPLC analysis .................................................................................... 161 Table S2. The IC50 values and predicted ΔG (kcal/mol) of LLX (36) and dual-functional inhibitors ........................................................................ 164 Table S3. The proposed structures of ESI–MS fragments of complex 41 .............. 165 Table S4. The proposed structures of ESI–MS fragments of complex 42/43 ......... 168 Table S5. The proposed structures of ESI–MS fragments of complex 44 .............. 169 | |
| dc.language.iso | zh-TW | |
| dc.title | 雙重抑制劑樂瓦斯他汀–羥胺之結構修飾：改變鋅結合基團及合成金屬錯合物 | zh_TW |
| dc.title | HDAC–HMGR Dual Inhibitors: Lovastatin–Hydroxamate with Varied Zinc-binding Groups and Metallo-Complexes | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 102-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 詹益慈(Yi-Tsu Chan),陳青周(Ching-Chow Chen),林榮信(Jung-Hsin Lin),簡敦誠(Tun-Cheng Chien) | |
| dc.subject.keyword | 組蛋白去乙醯?,3-羥基-3-甲基戊二酸輔?A還原?,樂瓦斯他汀,羥胺,鋅結合基團,雙重抑制劑,金屬錯合物, | zh_TW |
| dc.subject.keyword | HDAC,HMG-CoA reductase,Lovastatin,Hydroxamate,Zinc binding group,Dual-functional inhibitor,Metallo-complex, | en |
| dc.relation.page | 176 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2014-08-11 | |
| dc.contributor.author-college | 理學院 | zh_TW |
| dc.contributor.author-dept | 化學研究所 | zh_TW |
| 顯示於系所單位： | 化學系 | |
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|---|---|---|---|
| ntu-103-1.pdf 目前未授權公開取用 | 7.11 MB | Adobe PDF |
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