臺灣博碩士論文加值系統

雖然，含氟酮類化合物抗菌的結構活性關係已被廣泛研究，但在最佳取代位置C-7上影響效價，抗菌範圍，溶解度及藥效動力學方面則尚不清楚。本文目前研究探討的是導入活性官能基以合成一些norfloxacin類衍生物並評估其活性，諸如在C-7的piperazine環的第四位置氮上導入類以提供氫鍵與細菌體內的標的物DNA旋轉產生作用，以增加抗菌效價及抗菌範圍。初步結果(1)7-[4-(2-oxoethyl)piperazin-1-yl]衍生物12和13(含R-C=O部份)對於抗菌及細胞毒兩者均不具活性，然而2-imino-ethyl其類似物14 和15(含R-C=N-OH部份)對於抗菌及細胞毒兩者均具活性，並且對腎癌細胞株UO-31及CAKI-1展現出細胞毒的選擇性；(2) 2-iminoethyl衍生物14 和15尤其對methicillin抗性的葡萄球菌(S. aureus M-R)更具活性；(3)基取代(R-C=N-NH2)比類似的基取代(R-C=N-OH)更有活性，而基取代又比甲氧基取代有活性(R-C=N-OCH3)；(4)第八位置氟取代的衍生物(13和15)相對於未取代的衍生物(12和14)是較好的抗菌劑。
此外，本研究中也製備含α-次甲基-γ-丁基內酯環的類似物，希望利用α-次甲基-γ-丁基內酯環活性部份能提供額外的共價鍵能力與DNA旋轉結合。這些化合物針對九類六十種人類的細胞株評估其活體外活性，證實不僅對白血球細胞癌有強力活性而且對某些固形癌細胞有良好抑制活性。以氧為架橋的衍生物24a和24b同時展現細胞抑制(GI50值分別是6.31μM和1.51μM)及細胞毒殺(LC50值分別是50.1μM和11.7μM)效果，而以piperazine為架橋的類似物20f和20d只有弱的細胞抑制(GI50值分別是6.46μM和18.2μM；LC50 >100μM)能力。這些化合物中24b最有活性，對白血球癌細胞，SW-620 (結腸癌細胞)，LOXIMV1和SK-MEL-28(黑色素癌細胞)，GI50值分別是0.17μM，0.19μM， 0.30μM ，0.30μM

Although the structure-activity relationships of antibacterial fluoroquinolones have been extensively investigated, the optimum substituent at C-7 position which has a great impact on potency, spectrum, solubility and pharmacokinetics has not been precisely defined. The present study describes the preparation and evaluation of certain norfloxacin derivatives with an additional functional moiety such as 4-hydroxyaminoalkyl (R-C=N-OH) on the C-7 piperazin-1-yl group, with the aim of providing extra hydrogen-bonding capabilities with the target DNA gyrase and therefore,to increase potency and broaden the antibacterial spectrum. Preliminary results are (1) 7-[4-(2-oxoethyl)piperazin-1-yl]- derivatives 12 and 13 (with a R-C=O moiety) are inactive for both antibacterial and cytotoxic activities while their 2-iminoethyl counterparts 14 and 15 (R-C=N-OH) are active for both, and exhibited selective cytotoxicities against the growth of UO-31 and CAKI-1 renal cancer cells; (2) 2-iminoethyl derivatives 14 and 15 are especially active against methicillin resistant S. aureus (S. aureus M-R); (3) an amino substituent (R-C=N-NH2) is more active than its hydroxy counterpart (R-C=N-OH) which in turn is more potent than a methoxy substituent (R-C=N-OMe); (4) 8-fluoro derivatives (13 and 15) are more active antibacterial agents than their respective unsubstituted counterparts (12 and 14).
In addition, we have also prepared α-methylene-γ-butyrolactone-bearing analogues in hope that α-methylene-γ-butyrolactone moiety will provide an extra covalent bonding capability with DNA gyrase. These compounds were evaluated in vitro against 60 human tumor cell lines derived from nine cancer cell types and demonstrated not only strong growth inhibitory activities against leukemia cancer cells but also a fairly good activities against the growth of certain solid tumors. The oxygen-bridged derivatives 24a and 24b exhibited both cytostatic (GI50 value of 6.31μM and 1.51 μM respectively) and cytocidal (LC50 value of 50.1μM and 11.7 μM respectively) effects while the piperazine-bridged analogues 20f and 20d possessed only weak cytostatic (GI50 value of 6.46μM and 18.2μM respectively; LC50 value of > 100μM ) capability. Among them, 24b is the most potent, with GI50 value of 0.17μM , 0.19μM , 0.30μM and 0.30μM against leukemia, SW-620 (colon), LOXIMV1, and SK-MEL-28 (melanoma) cancer cells respectively

封面
中文摘要
英文摘要
致謝
目錄
圖目錄
表目錄
第一章 緒論
第一節 前言
第二節 研究動機
第二章 研究方法與步驟
（一） Norfloxacin之合成
（二） Ciprofloxacin 之合成
（三）1-Ethy1-6fluoro-7-[4-(2-substituted-2-oxoethy1)-1-piperaziny1]-4-oxo-1,4-dihydroquinoline-3-carboxylic acids之合成
（四）1-Ethy1-6fluoro-7-[4-(2-substituted-2-hydroxyimino)-1-piperaziny1]-4-oxo-1,4-dihydroquinoline-3-carboxylic acids之合成
（五）1-Ethy1-6fluoro-7-[4-(2-substituted-2-methoxyimino)-1-piperaziny1]-4-oxo-1,4-dihydroquinoline-3-carboxylic acids之合成
（六） 1-Ethy1-6fluoro-7-[4-(2-substituted-2-hydrazino)-1-piperaziny1]-4-oxo-1,4-dihydroquinoline-3-carboxylic acids之合成
（七）1-Ethy1-6fluoro-7-{4-[(2-substituted-2-,3,4,5-tetrahydro-4-methylene-5-oxo-2-furany1)methy1]piperaziny}-4-oxo-1,4-dihydroquinoline-3-carboxylic acids 之合成
（八） 1-Ethy1-6-fluoro-7-{4[(2-substituted-2,3,4,5-tetrahydro-4-methylene-5-oxo-2-furany1)methoxy-4-oxo-1,4-dihydroquinoline-3-cardboxylic acids之合成
（九） 1-Cyclopropy1-6-fluoro-7-[4-(2-substituted-2-oxoethy1)-1-piperaziny1]-4-oxo-1,4-dihydroquinoline-3-carboxylic acids之合成
（十） 1-Cyclopropy1-6-fluoro-7-[4-(2-substituted-2-hydroxyimino)-1-piperaziny1]-4-oxo-1,4-dihydroquinoline-3-carboxylic acids之合成
（十一） 1-Substituted-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperaziny1)quinoline-3-carboxylic acids之合成
（十二）1-(Substituted-benzy1)-7-(substituted-ether)-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acids之合成
（十三）Bis-fluoroquinolones之合成
第三章 實驗部分
第一節 儀器與試藥
第二節 生物活性試驗
（一） 抗菌活性試驗
（二） 細胞毒活性試驗
第四章 結果與討論
（一） 抗菌活性結果與討論
（二） 細胞毒活性結果與討論
（三） 化合物製備
（四）1-Ethyl-6-fluoro-7-[4-(2-substituted-2-hydroxyimino)-1-piperazinyl]-4-oxo-1,4-dihydioquinoline-3-carboxylic acids(14a-g,15a-f)之製備
（五）1-Ethyl-6-fluoro-7-[4-(2-substituted-2-methoxyimino)-1-piperazinyl]-4-oxo-1,4-dihydioquinoline-3-carboxylic acids(16a-g,17a-f)之製備
（六）1-Ethyl-6-fluoro-7-[4-(2-substituted-2-hydrazino)-1-piperazinyl]-4-oxo-1,4-dihydioquinoline-3-carboxylic acids(18a-g,19a-f)之製備
（七）1-Ethyl-6-fluoro-7-{4-[2-substituted-2,3,4,5-tetrahydro-4-methylene-5-oxo-2-furanyl)methyl]piperaziny}-4-oxo-1,4-dihydroquinoline-3-carboxylic acids(20a-g,22a-b)之製備
（八）1-Ethyl-6-fluoro-7-{4-[2-substituted-2,3,4,5-tetrahydro-4-methylene-5-oxo-2-furanyl)methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acids(24a-b)之製備
（九）1-Cyclopropyl-6-fluoro-7-[4-(2-substituted-2-oxoethyl)-1-piperaziny]-4-oxo-1,4-dihydroquinoline-3-carboxylic acids(26a-d)之製備
（十）1-Cyclopropyl-6-fluoro-7-[4-(2-substituted-2-hydroxyimino)-1-piperaziny]-4-oxo-1,4-dihydroquinoline-3-carboxylic acids(26a-d)之製備
（十一）1-Substituted-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)quinoline-3-carboxylic acids(27a-b,28a-b,29a-b,30a-b)之製備
（十二）1-(substituted-benzyl)-7-(substituted-ether)-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acids(32a-I)之製備
（十三）Bis-fluoroquinolones(35a-d)之製備
第五章 結論
參考文獻
研究成果目錄
（一）投稿論文
（二）學會發表論文
附錄

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