臺灣博碩士論文加值系統

腫瘤血管新生在癌症病程中扮演了重要的角色，當腫瘤體積大於2 mm3時，便需要新生的血管來提供氧氣及養份、移除代謝產生的廢物，以及提供腫瘤細胞轉移所需路徑。本研究的藥物設計融合五員雜環之2-吡咯啶酮與 (2-側氧吲哚啉-3-亞基)甲基吡咯，保留了二乙基胺的結構，並修飾吲哚酮之C(5) 位置取代基，來建立其構效關係 (structure-activity-relationships，SARs)。在離體抑人類結腸癌細胞株 (HCT116) 試驗中，合成產物12顯示良好的抑制活性及選擇性 (IC50 = 0.54 M；SI = 21.93)；相較於臨床用小分子抗血管新生藥物sunitinib，合成產物8-12、16與22-24之VEGFR-2、PDGFR及aurora A的離體抑制活性皆有顯著的提升；且11、12、23及24之離體血管新生抑制活性極佳。藉由融合五員雜環之2-吡咯啶酮可有效提升(2-側氧吲哚啉-3-亞基)甲基吡咯類似物之抑制VEGFR-2、PDGFR及aurora A的活性；不同的C(5) 位置取代對五員雜環融合之(2-側氧吲哚啉-3-亞基)甲基吡咯衍生物的生物活性，扮演著極重要的角色，其中又以C(5)-Br (11)、C(5)-I (12)、C(5)-OH (23)及C(5)-SH (24)最具潛力。本研究提供了一個新的小分子受體酪胺酸激酶抑制劑設計及發展方向。

Signaling pathways of VEGFs and PDGFs are crucial in tumor angiogenesis, which is essential in solid tumor progression and metastasis. This study reports our strategy for design and synthesis of a series of novel 2-pyrrolidone-fused (2-oxoindolin-3-ylidene)methylpyrrole derivatives as potential multi-target tyrosine kinase receptor inhibitors. The target compounds were obtained by condensation of 5-substituted oxindoles with N-substituted 2-pyrrolidone aldehyde 7 in satisfactory yields. Of these, 11, 12, 23 and 24 had the highest potency and, compared to sunitinib, showed: (1) significant increase in anti-proliferation of various cancer cells with a favorable selective index (SI); (2) higher inhibitory potency against both VEGFR-2 and PDGFRβ. The molecular modeling results showed that, in terms of VEGFR-2 binding, the synthetic products had a similar binding mode to sunitinib but with tighter interaction. The experimental results suggest that 11, 12, 23 and 24 might be promising anti-angiogenesis agents.

目錄 I
圖目錄 III
表目錄 VIII
附圖目錄 IX
中文摘要 XIII
Abstract XV
第一章 緒論 1
第一節 癌症 1
第二節 腫瘤與血管新生 6
第三節 受體酪胺酸激酶 8
第四節 酪胺酸激酶抑制劑 11
第五節 研究目的 16
第六節 研究方法 20
第二章 材料與方法 34
第一節 實驗儀器 34
第二節 試藥與溶媒 35
第三節 細胞來源 39
第四節 化學合成 40
第五節 生物活性 52
第六節 分子模擬 59
第三章 實驗結果 60
第一節 合成中間產物 60
第二節 合成終產物 67
第三節 生物活性 91
第四節 分子模擬 111
第四章 討論 114
第一節 化學合成 114
第二節 生物活性 127
第三節 分子模擬 135
第五章 結論 136
第六章 參考文獻 138
附圖 148
附錄 研究成果 174

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