中文摘要  抗微管劑

微管蛋白聚合抑制劑之研究 :1-Benzenesulfonyl-7-arylcarboxamido-1H-indoles 之合成

 中文摘要

 抗微管劑 E7010(ABT-751) 作用在細胞週期的 M phase ， in vitro 對 c olon 38 癌細胞株的 IC50 為 0.29μg/ml ，主要作用在微管蛋白的 colc hicine binding site ，對 vinca alkaloid 有抗藥性的二種 P388 細胞株具 活性，且同時具抑制腫瘤血管的活性。 E7010 具有良好的口服藥物動 力學性質，及較低的副作用，即使藥效不高仍有機會成為藥物， E70 10 目前 (2004) 正在美國進行第二期臨床試驗。

 在論文中係以 E7010(ABT-751) 為標的化合物，進行構造修飾以期製

造更有效之抗癌化合物。合成反應以 7-nitroindole 為起始原料，經親

核性加成反應，硝基還原和醯胺生成，等三個步驟合成了 12 個 1-ben

zenesulfonyl-7- arylcarboxamides-1H-indole 化合物，並以人體口腔癌 K

B 細胞株進行抗癌活性測試，其中化合物 30 為一個以五環雜環為支

鏈的化合物具有顯著活性，其 IC50 達 0.06μM ，並且有三個化合物 (2

7, 28, 31) 有中等活性。未來我們將進行更多細胞株的活測試及相關化

合物的合成，以進一步確認活性。

Synthesis of 1-Benzenesulfonyl-7-arylcarboxamido-1H-indoles as Tubulin Polymerization Inhibitor

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英文摘要

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The anti-microtubule agent, E7010(ABT-751) is acting on the M phase in cell proli feration cycle. E7010 showed in vitro activity with a IC50 of 0.29μg/ml in colon 38 cancer cell line. The major effect of E7010 is binding to colchicine binding site of t he tubulin and active against two kinds of vinca alkaloid-resistant P388 cell lines. It also appeared to have a tumor specific antivascular activity. E7010 has good oral p harmacokinetic profile and its side effects are minimum. E7010(ABT-751) is now u nder phase II clinical trial against several solid tumors in the United States.

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In this paper, E7010 was selected as the molecule target for the further structural m

odification and try to synthesize a series of its analogues to evaluate the anti-tumor

activity. 7-Nitroindole as starting material via three step reactions including the nuc

leophilic addition, nitro reduction and amide formation to afford twelve compounds

( 25~36) of 1-benzenesulfonyl-7-arylcarboxamido-7- 1H-indoles. The anti-prolifera

tion of the modified compounds were evaluated in human oral epidermoid carcino

ma cell. The most potent compound of 30 showed a IC50 of 0.06μM. Other three c

ompounds of 27, 28 and 31 also showed a promising result and are active in anti-tu

mor activity.