合成及結構與活性關係之1-磺基苯-6氮基吲哚類有效抗癌化合物

Synthesis and Structure-Activity Relationship of 1-Benzenesulfonyl-6-Azaindoles as Potent Anticancer Agents

蘇民傑(Min-Jie Su)

指導教授 ： 劉景平

臺北醫學大學/藥學院/藥學研究所/碩士(2007年)

摘要

我們以N-[2-[(4-hydroxyphenyl)amino]-3-pyridinyl]-4- methoxybenzene- sulfonamide（ABT-751）為骨架進行修飾，合成出兩個新的系列7-苯胺基-6-氮基吲哚-1-磺胺和7-苯基-6-氮基吲哚-1-磺胺為具有抗增生活性的化合物。ABT-751是透過和微小管上的秋水仙素鹼鍵結位置鍵結產生作用的口服有活性的抗癌化合物。現正在美國進行人體臨床試驗第二期。7-苯胺基-6-氮基吲哚-1-磺胺類衍生物的合成是以2-溴基-3-硝基嘧啶為起始物，接著使用乙烯基鎂溴反應得到7-溴基-6氮基吲哚。將七號位碳上的溴基取代成各種苯胺類衍生物，再與4-甲氧基-磺基氯苯反應得到6-氮基吲哚-1-磺胺。7-苯基-6-氮基吲哚-1-磺胺類衍生物的合成是以7-溴基-6氮基吲哚-1-磺胺為起始物和各種苯硼酸經由鈴木偶合反應在第七號位碳上，得到在第七號位碳上有苯基取代的6-氮基吲哚-1-磺胺。化合物2, 3 , 4 , 5 , 9 , 10和14具有中等的毒殺細胞能力，IC50 在278-886 nM之間。化合物7 , 11 , 13和ABT-751的IC50 208 nM比較起來，在活性上有輕微的增加，IC50 在150-200 nM之間。最有活性的化合物8，在人類口腔上皮腫瘤細胞株的IC50 達到80 nM。在結構與活性的關係資訊中顯示，7-苯基-6-氮基吲哚-1-磺胺類衍生物的活性比7-苯胺基-6-氮基吲哚-1-磺胺類衍生物的活性好。這些發現鼓舞我們繼續研究6-氮基吲哚-1-磺胺這類化合物，更進ㄧ步的去探討它的抗增生機轉。

關鍵字

氮基吲哚磺胺 ； ABT-751 ； 抗癌藥

並列摘要

Two novel series of 7-anilino-6-azaindole-1-sulfonamides and 7-aryl-6- azaindole-1-sulfonamides based on N-[2-[(4-hydroxyphenyl)amino]-3- pyridinyl]-4-methoxybenzenesulfonamide (ABT-751) as a template were synthesized as potent antiproliferative agents. ABT-751 is an orally-active anticancer agent acting through the binding with the colchicine binding site on the tubulin. It is now undergoing human clinical trial. The synthesis of 7-anilino-6-azaindole-1-sulfonamide derivatives started from 2-bromo-3- nitropyridine, which was subjected to the vinyl magnesiumbromide to give 7-bromo-6-azaindole. The 7-bromo group was replaced with various aniline, and then treated with 4-methoxybenzenesulfonyl chloride to afford the 6-azaindole-1-sulfonamides.The synthesis of 7-aryl-6- azaindole-1- sulfonamide derivatives were prepared by a Suzuki reaction at 7-position, utilizing the 7-bromo-6-azaindole was treated with a variety of phenylboric acid to give the designed 7-aryl substituted 6-azaindoles. Compound 2, 3 , 4 , 5 , 9 , 10 , and 14 displayed moderate cytotoxicities with IC50 values of 278-886 nM. Compound 7 , 11 , and 13 showed a slight increase in activity with IC50 values of 150-200 nM as compared to ABT-751 (IC50 = 208 nM). The most potent compound 8 showed potent antiproliferative activity with IC50 values of 80 nM against human KB oral epidermoid carcinoma cell line. Structure- activity relationship information revealed that 7-aryl-6- azaindole-1- sulfonamide derivatives was more potent than 7-anilino-6-azaindole-1- sulfonamide derivatives. These findings have encouraged us to extensively explore the novel 6-azaindole-sulfonamides and further investigate their mode of action and mechanism.

並列關鍵字

azaindole ； sulfonamide ； ABT-751 ； anticancer drugs

參考文獻

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