設計與合成1,4-二甲基咔唑及橢圓玫瑰樹鹼之
苯磺醯胺衍生物作為潛能抗癌試劑

為了發展出強效的細胞週期抑制劑，本論文將以E7010為起始模板進行結構修飾。根據固定構型設計概念，E7010中連接兩芳香環之可旋轉的二級胺鍵結將被固定。根據此設計構想合成了一系列1,4-二甲基咔唑苯磺醯胺衍生物。生物活性測試結果顯示，化合物18a展現強效的抑癌效果，其對於HeLa、HT-29及Hep3B腫瘤細胞呈現GI50為0.02至0.07 µM的卓越抑制活性。另外，咔唑苯磺醯胺衍生物26b亦呈現良好的抑癌活性，其對於A549腫瘤細胞呈現GI50為0.08 µM的抑制活性。磺醯胺結構上取代甲基及乙基之化合物22a及23a不僅保持強效之生物活性，對於AGS及PC-3腫瘤細胞，甚至呈現更有效的抑制活性。由於橢圆玫瑰樹鹼之四環平面結構包含1,4-二甲基咔唑特徵，為了提高苯磺醯胺衍生物18a之抗癌活性，本論文將化合物18a之1,4-二甲基咔唑置換成橢圆玫瑰樹鹼，合成了一系列橢圆玫瑰樹鹼苯磺醯胺衍生物30。雖然其生物活性測試結果並未呈現強效的癌細胞抑制活性，但是橢圆玫瑰樹鹼第7位卻是值得繼續探索並發展更有效的腫瘤細胞抑制劑。欲求提高Saxton合成橢圆玫瑰樹鹼全合成之產率，本論文運用微波於橢圆玫瑰樹鹼之全合成。透過單槽式合法法合成二級胺化合物47，可以有效地降低反應時間並提高合成產率，全合成總產率提升約10倍。為求更高反應產率，較低產率的D環環化步驟，因為二級胺結構轉化成甲基苯磺胺結構56後，大大地提升其環化產率至75%，全合成總產率提升約25倍。為了將微波廣泛地運用於橢圆玫瑰樹鹼衍生物合成中，微波亦應用於9-溴化橢圆玫瑰樹鹼及9-硝基橢圆玫瑰樹鹼合成中，皆能獲得良好的反應產率。

關鍵字

橢圓玫瑰樹鹼；二甲基咔唑；微波

並列摘要

Abstract An attempt to develop potent agents to arrest cell cycle, E7010 (6) was chosen as the lead compound. Based on conformational restriction approach, to constrain the secondary amine linkage between pyridine and benzene in E7010 was proposed. Accordingly, 1,4-dimethylcarbazole motif was considered to be an essential scaffold. In the result, 18a demonstrated activities against several cancer cell lines, especially for HeLa, HT-29 and Hep3B cancer cell lines with GI50 in the range of 0.02 to 0.07 µM. Besides, carbazolyl sulfonamide 26b also exhibited potent cytotoxic activities. It inhibited A549 cell with GI50 at 0.08 µM. Compounds containing methyl (22a) and ethyl (23a) on sulfonamide nitrogen lead to not only enhance the potency but also to provide better activities against AGS and PC-3 cell lines. Since ellipticine has a common skeleton of 1,4-dimethylcarbazole, to promote the activities of 18a, the 1,4-dimethylcarbazole of 18a was replaced with ellipticine. Therefore, ellipticine derivatives within benzenesulfonamide are developed. According to the initial biological assays, the attachment of benzenesulfonamide to ellipticine reduced the activities. Although ellipticine sulfonamide (30) didn’t demonstrate promising results, the research focus on the C-7 of ellipticine is still interesting. To explore the substituents on this position may provide opportunity to search potent anticancer agents. To improve the total synthesis of ellipticine based on Saxton’s approach, the one-pot synthesis of secondary amine 47 is considered to shorten the reaction time and improve the reaction yield compared to original approach. The long-lasting problematic low yield in the D-ring cyclization of ellipticine (27) by Saxton’s approach was dramatically improved through N-(1,4-dimethylcarbazol-3-ylmethyl)-N-tosylaminoacetaldehyde diethyl acetal (56) with microwave irradiation. The yield of D-ring cyclization of ellipticine was improved to 75%. The overall yield of ellipticne starting from indole was signiﬁcantly increased by 25-folds. Microwave was also used in the synthesis of 9-bromoellipticine and 9-nitroellipticine. Hence, this new approach is superior to reported methods in yields, reaction time, and it provides efficient access to a broad spectrum of ellipticine derivatives.

並列關鍵字

ellipticine ； dimethylcarbazole ； microwave

參考文獻

Chen, C. S; Lai, S. Y.; Hsu, P. S..; Tsai, C. Y.; Fang, C. W.; Su, M. J.; Cheng, F. C.; Kao, C. L.; Chern, J. W. Design, synthesis and biological evaluation of heterocycle-conjugated styrene derivatives as protein tyrosine kinase inhibitors and free radical scavengers. Chin. Pharm. J. 2002, 54, 353-374.

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設計與合成1,4-二甲基咔唑及橢圓玫瑰樹鹼之苯磺醯胺衍生物作為潛能抗癌試劑

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