雙環磺胺雜環類抗癌化合物之合成和結構與活性關係的研究
中文摘要
以生物等效性的概念為基礎，先前已將 N-[2-[(4-hydroxyphenyl)amino]-3-pyrid
inyl]-4- methoxybenzene- sulfonamide （ ABT-751 ）此基本骨架進行修飾，合
成出兩個新系列 7- 苯胺基 -6- 氮基吲哚 -1- 磺胺和 7- 苯基 -6- 氮基吲哚 -1- 磺
胺且均具抗增生活性之化合物。 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。在先前的研究中發現 7- 苯基 -6- 氮基吲哚 -1- 磺胺類衍生物的
活性較 7- 苯胺基 -6- 氮基吲哚 -1- 磺胺類衍生物的活性強，於是更進一步研究
其抗增生機轉與結構之間關係，另合成了 7- 苯基吲哚 -1- 磺胺和 7- 苯基二氫
吲哚 -1- 磺胺。 7- 苯基吲哚 -1- 磺胺類衍生物是以 1- 溴基 -2- 硝基苯與乙烯基
鎂溴反應後與 4- 甲氧基 - 磺基氯苯反應得到 7- 溴基吲哚 -1- 磺胺。七號位碳
上溴基與各種苯硼酸進行鈴木偶合反應即可得到 7- 苯基吲哚 -1- 磺胺。 7- 苯
基二氫吲哚 -1- 磺胺類衍生物是將 1- 溴基 -2- 硝基苯與乙烯基鎂溴反應後得到
之 7- 溴基吲哚以氰基硼氫化鈉還原後與 4- 甲氧基 - 磺基氯苯反應得到 7- 溴
基二氫吲哚 -1- 磺胺。七號位碳上溴基再與各種苯硼酸進行鈴木偶合反應得到
7- 苯基二氫吲哚 -1- 磺胺。化合物 1, 2, 4, 5, 9, 11, 12, 14, 15, 23 及 24 表現出
強效抗癌活性， IC50 在 15-50 nM 之間。而其結構與活性的關係顯示 7 位碳
上接有拉電子基之苯環或五員、六員雜環皆可增加其活性，但真正之機轉仍
待進一步確立。
Synthesis and Structure-Activity Relationships of Biphenyl-Sulfonamides Heterocycles as Anticancer Agents
英文摘要
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. Based on the more potent antiproliferative activity of 7-aryl-6-azaindole-1-sulfonamides, another two novel series of 7- arylindole-1-sulfonamides and 7-arylindoline-1-sulfonamides were synthesized. The synthesis of 7-aryl-6-azaindole-1-sulfonamide derivatives started from 2-bromo-3-nitropyridine, which was subjected to the vinyl magnesium bromide to give 7-bromo-6-azaindole, treated with 4-
methoxybenzenesulfonyl chloride to afford the 6-azaindole -1-sulfonamides. 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. 7-arylindole-1-sulfonamides and 7-arylindoline-1-sulfonamide derivatives were prepared started from 1-bromo-2- nitrobenzene by the same procedure. Three types of core structure analogous, for example, 7-aryl-6-azaindoles (20-24), 7-arylindoles (18-19) and 7-
arylindolines (1-17) were evaluated their antiproliferative activity against oral epidermoid carcinoma KB cells. In the preliminary data, compounds 1, 2, 4, 5, 9, 11, 12, 14, 15, 23, and 24 demonstrate substantial activity with IC50 values ranging from 15-50 nM. Structure- activity relationship information revealed that 7-aryl-6- azaindole-1- sulfonamide and 7-arylindoline-1-sulfonamide derivatives were more potent than 7- arylindole-1-sulfonamide derivatives. These findings have encouraged us to extensively explore these two novel sulfonamides and further investigate their mode of actions and mechanisms.
