請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/101437完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 李宗徽 | zh_TW |
| dc.contributor.advisor | Tzong-Huei Lee | en |
| dc.contributor.author | 顧家瑋 | zh_TW |
| dc.contributor.author | Andrea Gu | en |
| dc.date.accessioned | 2026-02-03T16:16:56Z | - |
| dc.date.available | 2026-02-04 | - |
| dc.date.copyright | 2026-02-03 | - |
| dc.date.issued | 2026 | - |
| dc.date.submitted | 2026-01-26 | - |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/101437 | - |
| dc.description.abstract | 本研究主軸為利用高解析串聯質譜技術數據衍生之特徵化化學分子網絡分析 (feature-based molecular networking, FBMN)方法，對天然萃取物進行代謝體特徵探討，鎖定特定骨架之潛力活性成分進行導引性分離純化、構造鑑定及其活性確認。海洋藻源內生真菌哈氏木黴菌經一株多化合物發酵策略 (one strain many compounds, OSMAC)結合FBMN分析選定發芽玄米培養基大量發酵。發酵產物以甲醇萃取濃縮得到甲醇萃取物，經乙酸乙酯及水分配獲得乙酸乙酯層及水層。乙酸乙酯層以矽膠管柱進行梯度沖提，得到之分劃經FBMN分析鎖定萜類化合物進行分離純化，並透過HRESIMS、NMR、UV、IR與 X光單晶繞射等方法進行結構解析，獲得2個新化合物trichospirol A (THN1)與trichospirol B (THN2)，以及12個已知化合物 (THN3–THN14)。新化合物並進行生合成路徑推衍，且其與前驅物α-bisabolol 及trans-nerolidol位於同一FBMN群集，顯示其前驅物於發酵產物中的存在，具生合成推導及FBMN於天然物化學研究之應用價值。其中8個足量化合物 (THN1、THN2、THN5–THN7、THN9–THN11)以小鼠離體胸主動脈芽管模型進行抑制血管新生活性測試，測試濃度為 20 µM。結果顯示相較於對照組 (1.00 ± 0.11-fold)，5-hydroxy-3-hydroxymethyl-2-methyl-7-methoxychromone (THN7) (0.57 ± 0.12-fold)與ergosterol peroxide (THN11) (0.20 ± 0.12-fold)顯著抑制血管新生，而trichospirol A (THN1)則促進血管新生 (2.05 ± 0.48-fold)。8個化合物並以人類視網膜母細胞瘤細胞株Y79評估其抗癌活性，作用時間48 小時後，相較於對照組 (1.00 ± 0.13-fold)，ergosterol peroxide (THN11)可顯著抑制Y79細胞增殖 (0.75 ± 0.03-fold)，且具有劑量-活性相關性 (IC50 = 35.3 ± 6.9 µM)。濱海鹽生植物馬氏濱藜全株陰乾後以甲醇萃取濃縮得到甲醇萃取物，利用正己烷、正丁醇及水進行分配，獲得正己烷、正丁醇及水層。正己烷及正丁醇層分別進行管柱梯度沖提，獲得之分劃進行FBMN分析。配合FBMN結果，鎖定正己烷層及正丁醇層內特定分劃中具開發潛力之三萜類化合物及葉綠素類化合物進行分離純化及結構解析，共獲得8個新化合物atriplexosaponins A–D (AM1–AM4)、atriplexoterpenes A–B (AM5–AM6)，atriplexophylls A–B (AM7–AM8)，以及13個已知化合物 (AM9–AM21)，其中AM7及AM8為兩個首次分離並經NMR確認之立體異構物。18個足量化合物 (AM1–AM17、AM19)進行人類結腸直腸癌細胞株 (HT-29及HCT-116)活性測試，atriplexophyll A (AM7)抑制活性IC50為0.14-0.33 μM，atriplexophyll B (AM8)為7.95-8.81 μM。SAR討論結果顯示葉綠素結構之pyran ring為抗癌活性重要官能基。本研究成功利用特徵化化學分子網絡分析策略，經導引性分離純化，由海洋藻源內生真菌哈氏木黴菌及濱海鹽生植物馬氏濱藜獲得目標活性化合物。研究結果顯示哈氏木黴菌具有豐富之抗視網膜母細胞瘤增生化合物，可發展利用真菌發酵大量產生活性先導化合物，而馬氏濱藜之大量三萜類成分及活性葉綠素，可提升濱海植物馬氏濱藜之利用價值。上述之研究成果，提供了海源天然物藥物開發的可能性，對臺灣海源天然物資源應用有所貢獻。 | zh_TW |
| dc.description.abstract | This study applies Feature-Based Molecular Networking (FBMN), constructed from high-resolution tandem mass spectrometry (HRMS/MS) data, to visualize the natural product metabolome profile in crude extracts. The analysis targets putatively bioactive molecular scaffolds for FBMN-guided fractionation, purification, and validation of bioactivity. The work comprised two parts: (A) a chemical investigation of a marine algae-derived endophytic fungus, Trichoderma harzianum Rifai NTU2180, along with bioactivity assays relevant to retinoblastoma, and (B) a chemical investigation of the coastal halophyte Atriplex maximowicziana Makino with its anti-colorectal cancer activities. For the marine algae-derived endophytic fungus T. harzianum, an OSMAC (one strain many compounds) strategy was integrated with FBMN analysis. The germinated brown rice (GBR) cultivation condition was subsequently selected for scale-up fermentation. The fermented products were extracted with methanol, and the crude extract was partitioned between ethyl acetate (EtOAc)and water, affording an EtOAc layer and a water layer. The EtOAc layer was subjected to silica gel column chromatography with gradient elution to yield 15 fractions. Based on the FBMN analysis of fractions, targeted molecular structure families were selected, guiding the isolation and purification. Structural elucidation was accomplished by NMR, UV, IR, HRESIMS, and single-crystal X-ray diffraction, leading to the identification of two new compounds, trichospirols A (THN1) and B (THN2), along with 12 known compounds (THN3–THN14). A plausible biosynthetic pathway for the new isolates was proposed. Notably, the putative precursors α-bisabolol and trans-nerolidol co-clustered with the new compounds in FBMN, supporting both the biosynthetic rationale and the utility of FBMN in natural products research. To assess anti-retinoblastoma activities, eight compounds available in sufficient amount (THN1, THN2, THN5–THN7, and THN9–THN11) were tested at 20 µM. Anti-angiogenic activity was evaluated using an ex vivo mouse thoracic aorta sprouting assay, in which 5-hydroxy-3-hydroxymethyl-2-methyl-7-methoxychromone (THN7) (0.57 ± 0.12-fold of control) and ergosterol peroxide (THN11) (0.20 ± 0.12-fold of control) significantly inhibited angiogenesis, whereas trichospirol A (THN1) promoted sprouting (2.05 ± 0.48-fold of control). These eight compounds were also evaluated against the Y79 human retinoblastoma cell line. After 48 h of treatment, ergosterol peroxide (THN11) significantly suppressed Y79 cell proliferation to 0.75 ± 0.03 relative to the control group (1.00 ± 0.13), and exhibited a dose–dependent relationship with an IC₅₀ value of 35.3 ± 6.9 µM. For the coastal halophyte A. maximowicziana, the dried whole plant was extracted with methanol, and the crude extract was partitioned with n-hexane, n-butanol, and water to afford n-hexane, n-butanol, and water layers. The n-hexane and n-butanol layers were independently fractionated by gradient column chromatography. After investigating the FBMN of fractions, selected fractions enriched in triterpenoids and chlorophyll-related metabolites were prioritized for targeted isolation and purification, followed by comprehensive structure elucidation. Eight new compounds were obtained, including four triterpenoid saponins, atriplexosaponins A–D (AM1–AM4), two triterpenoids, atriplexoterpenes A–B (AM5–AM6), and two chlorophyll derivatives, atriplexophylls A–B (AM7–AM8), together with 13 known compounds (AM9–AM21). Notably, AM7 and AM8 were isolated as a pair of stereoisomers, and their structures were confirmed by NMR for the first time. Eighteen compounds with sufficient amount (AM1–AM17 and AM19) were further evaluated for the activity against human colorectal cancer cell lines (HT-29 and HCT-116). Atriplexophyll A (AM7) exhibited potent inhibitory activity with IC₅₀ values of 0.14–0.33 μM, while atriplexophyll B (AM8) showed IC₅₀ values of 7.95–8.81 μM. Structure–activity relationship (SAR) considerations suggested that the pyran ring embedded in the chlorophyll scaffold constitutes a key functional group contributing to anticancer potency. This study demonstrates that the FBMN-driven workflow accelerates the discovery of new and bioactive natural products through guided isolation and purification. The results indicate that T. harzianum is a source of active metabolites relevant to retinoblastoma and serves as a feasible fermentation platform for the scalable production of bioactive lead compounds. Meanwhile, the high content of triterpenoids and the existence of bioactive chlorophyll derivatives from A. maximowicziana enhance the utilization value of this coastal halophyte. Overall, these findings underscore the promise of marine-derived natural products for drug discovery and support the development and utilization of Taiwan’s marine natural product resources. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2026-02-03T16:16:56Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2026-02-03T16:16:56Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 口試委員會審定書 i
致 謝 ii 中文摘要 iv 英文摘要 Abstract vi 目 次 ix 圖 次 xii 表 次 xviii 縮寫表 Glossary of Abbreviations xix 第一章、緒論 1 第一節、哈氏木黴菌 (Trichoderma harzianum) 6 壹、哈氏木黴菌之介紹 6 貳、哈氏木黴菌過去成分回顧 7 參、哈氏木黴菌過去藥理文獻回顧 28 第二節、馬氏濱藜 (Atriplex maximowicziana) 33 壹、濱藜屬 (Atriplex)植物介紹 33 貳、濱藜屬植物過去成分回顧 35 參、濱藜屬植物過去藥理文獻回顧 51 第二章、研究動機與目的 53 第一節、哈氏木黴菌 (T. harzianum) 55 第二節、馬氏濱藜 (A. maximowicziana) 56 第三章、實驗結果 57 第一節、特徵化分子網絡分析、萃取、分離與化合物結構 57 壹、哈氏木黴菌 (T. harzianum) NTU2180 57 一、特徵化化學分子網絡分析 (feature-based molecular networking, FBMN) 57 二、哈氏木黴菌 (T. harzianum) NTU2180萃取分離與所得化合物總覽 61 三、Trichospirol A (THN1)與trichospirol B (THN2)之結構研究 65 四、Trichospirol A (THN1)與trichospirol B (THN2)生合成路徑推衍 80 貳、馬氏濱藜 (A. maximowicziana) 81 一、特徵化化學分子網絡分析 (feature-based molecular networking, FBMN) 81 二、馬氏濱藜 (A. maximowicziana)萃取、分離與所得化合物總覽 84 三、Atriplexosaponins A–D (AM1–AM4)之結構研究 90 四、Atriplexoterpene A (AM5)與atriplexoterpene B (AM6)之結構研究 119 五、Atriplexophyll A (AM7)與atriplexophyll B (AM8)之結構研究 132 第二節、生物活性試驗 146 壹、血管新生活性試驗 (aortic ring sprouting assays) 146 貳、抗人類視網膜母細胞瘤Y79細胞株活性試驗 148 參、抗人類結腸直腸癌細胞株HT-29與HCT-116細胞株活性試驗 149 第四章、討論 152 第一節、哈氏木黴菌 (T. harzianum) NTU2180 152 第二節、馬氏濱藜 (A. maximowicziana) 154 第五章、實驗部分 158 第一節、儀器與材料 158 第二節、菌種來源與保存 162 第三節、植物來源與樣本保存 163 第四節、活性試驗方法 164 壹、血管新生活性試驗 (aortic ring sprouting assays) 164 貳、抗人類視網膜母細胞瘤Y79細胞株活性試驗 164 參、抗人類結腸直腸癌HT-29及HCT-116細胞株活性試驗 165 第五節、特徵化化學分子網絡 (feature-based molecular networking, FBMN)分析 166 壹、哈氏木黴菌 (T. harzianum) NTU2180 GBR大量培養萃取物 166 貳、馬氏濱藜 (A. maximowicziana)全株萃取物 167 第六節、培養、萃取與分離 169 壹、哈氏木黴菌 (T. harzianum) NTU2180 169 貳、馬氏濱藜全株 (A. maximowicziana) 171 第七節、化合物數據 174 第六章、參考文獻 260 | - |
| dc.language.iso | zh_TW | - |
| dc.subject | 特徵化化學分子網絡 | - |
| dc.subject | 哈氏木黴菌 | - |
| dc.subject | 馬氏濱藜 | - |
| dc.subject | 萜類化合物 | - |
| dc.subject | 葉綠素類化合物 | - |
| dc.subject | 抗人類視網膜母細胞瘤 | - |
| dc.subject | 抗人類結腸直腸癌 | - |
| dc.subject | FBMN | - |
| dc.subject | Trichoderma harzianum | - |
| dc.subject | Atriplex maximowicziana | - |
| dc.subject | terpenoids | - |
| dc.subject | chlorophylls | - |
| dc.subject | anti-retinoblastoma | - |
| dc.subject | anti-colorectal cancer | - |
| dc.title | 化學分子網絡導向之哈氏木黴菌及馬氏濱藜成分及其活性研究 | zh_TW |
| dc.title | Molecular networking-driven investigation of chemical constituents and their bioactivities from Trichoderma harzianum Rifai and Atriplex maximowicziana Makino | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 114-1 | - |
| dc.description.degree | 博士 | - |
| dc.contributor.coadvisor | 吳和澄 | zh_TW |
| dc.contributor.coadvisor | Ho-Cheng Wu | en |
| dc.contributor.oralexamcommittee | 宋秉鈞;陳日榮;李慶國;鄭源斌;蕭哲志 | zh_TW |
| dc.contributor.oralexamcommittee | Ping-Jyun Sung;Jih-Jung Chen;Ching-Kuo Lee;Yuan-Bin Cheng;George Hsiao | en |
| dc.subject.keyword | 特徵化化學分子網絡,哈氏木黴菌馬氏濱藜萜類化合物葉綠素類化合物抗人類視網膜母細胞瘤抗人類結腸直腸癌 | zh_TW |
| dc.subject.keyword | FBMN,Trichoderma harzianumAtriplex maximowiczianaterpenoidschlorophyllsanti-retinoblastomaanti-colorectal cancer | en |
| dc.relation.page | 278 | - |
| dc.identifier.doi | 10.6342/NTU202600022 | - |
| dc.rights.note | 未授權 | - |
| dc.date.accepted | 2026-01-27 | - |
| dc.contributor.author-college | 生命科學院 | - |
| dc.contributor.author-dept | 漁業科學研究所 | - |
| dc.date.embargo-lift | N/A | - |
| 顯示於系所單位： | 漁業科學研究所 | |
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