臺灣博碩士論文加值系統

吲哚喹啉四環系統顯示很多的生物活性是組成天然產物重要結構的一部分。例如cryptolepine (一種吲哚[3,2-b]喹啉衍生物)和isocryptolepine (一種吲哚[3,2-c]喹啉衍生物)是兩種從非洲植物Cryptolepis sanguinolenta 的根部所分離出的吲哚喹啉化
合物。從cryptolepine 體外和體內廣泛的生物活性研究，展現出它的抗瘧疾、抗菌、抗發炎和當作抗癌藥劑廣泛的應用。而同質異構物isocryptolepine (也被提到當作cryptosanguinolentine)較少被引起注意。因此，本論文敘述一些吲哚[3,2-c]喹啉(isocryptolepine)衍生物的合成與抗增生評估。結果顯示，三種癌細胞株：子宮頸癌
細胞(HeLa)、肺癌細胞(A549)和肝癌細胞(SKHep)，易受影響的IC50 低於2.17 ?嵱，而前列腺癌細胞(PC-3)對於這些吲哚[3,2-c]喹啉有相當耐性。在這些化合物中，N,N-bis-[3-(11H-indolo[3,2-c]quinolin-6-yl)aminopropyl]amine hydrochloride (40)活性
最好，針對子宮頸癌細胞，肺癌細胞和前列腺癌細胞抑制50%的濃度分別為0.068、0.11、和0.08 ?嵱，也比對照組的doxorubicin 有更佳的活性。作用機轉研究指出，化合物40 誘導激活caspase-3，??-H2AX 磷酸化，poly(ADP-ribose) polymerase 的開裂和DNA 破碎。這些結果提供了DNA、topo I 和topoII 是吲哚[3,2-c]喹啉衍生物主要作用目標的證據，因而抑制增生和造成癌細胞的凋亡。

The tetracyclic indoloquinoline ring system constitutes an important structural moiety in
natural products exhibiting numerous biological activities. For example, cryptolepine (an
indolo[3,2-b]quinoline derivative) and isocryptolepine (an indolo[3,2-c]quinoline derivative)
are two indoloquinolines isolated from the roots of the african plant Cryptolepis sanguinolenta.
Extensive investigations on the in vitro and in vivo biological activities of cryptolepine
revealed its wide applications as anti-malarial, anti-microbial, anti-inflammatory, and
anticancer agents. The isomeric isocryptolepine (also referred to as cryptosanguinolentine),
however, attracted only limited attention. Therefore, this dissertation describes the synthesis
and antiproliferative evaluation of certain indolo[3,2-c]quinoline (isocryptolepine) derivatives.
Results indicated that three cancer cell lines, HeLa, A549, and SKHep, are very susceptible
with IC50 of less than 2.17 　?嵱 while PC-3 is relatively resistant to this group of
indolo[3,2-c]quinolines. Among them, N,N-bis-[3-(11H-indolo[3,2-c]quinolin-6-yl)
aminopropyl]amine hydrochloride (40) was the most active, with IC50 of 0.068, 0.11, and 0.08
?嵱 against the growth of HeLa, A549, and PC-3, respectively, which is more active than the
prevailing doxorubicin. Mechanism studies indicated compound 40 can induce caspase-3
activation, ??-H2AX phosphorylation, cleavage of poly(ADP-ribose)polymerase and DNA
fragmentation. These results provide evidence that DNA, topo I, and topo II are the primary
targets of indolo[3,2-c]quinoline derivatives and that consequently inhibits proliferation and
causes apoptosis in cancer cells.

Abstract ........................................................................................ 6
中文摘要 ....................................................................................... 7
壹、緒論 ....................................................................................... 8
貳、 研究背景及目的 ................................................................. 17
参、合成方法 .............................................................................. 25
一､吲哚[3,2-c]喹啉類之合成 ................................................................... 25
二､逆合成分析 ......................................................................................... 26
三､吲哚[3,2-c]喹啉類衍生物之合成 ....................................................... 26
肆、結果與討論 .......................................................................... 34
(一)體外抗癌活性測試 ............................................................................... 34
(二) DNA topoisomerases I 和II 抑制活性評估 ........................................ 42
(三) Hela cell 增生抑制作用和細胞群落產生評估 ................................... 43
(四) PC-3 cells 間接造成細胞凋亡途徑 .................................................... 45
(五) IQDMA 對K562 細胞G2/M phase arrest 作用機轉 .......................... 46
(六) IQDMA 對HL-60 細胞S-phase arrest 作用機轉 .............................. 51
伍、結論 ..................................................................................... 57
2
陸、合成實驗部分 ...................................................................... 58
一、溶劑 ..................................................................................................... 58
二、儀器 ..................................................................................................... 58
三、試藥 ..................................................................................................... 59
四、化合物製備 ......................................................................................... 63
柒、參考文獻 ............................................................................ 114
捌、論文著作 ............................................................................ 119
一、論文相關著作 ................................................................................... 119
二、參考論文 ........................................................................................... 119
三、研討會論文 ....................................................................................... 121
四、專利 ................................................................................................... 123

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