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 colchicine 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， E7010 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-benzenesulfonyl-7- arylcarboxamides-1H-indole 化合物，並以人體口腔癌 KB 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 (27, 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

英文摘要 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 the 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 pharmacokinetic profile and its side effects are minimum. E7010(ABT-751) is now under phase II clinical trial against several solid tumors in the United States.

In this paper, E7010 was selected as the molecule target for the further structural modification 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 nucleophilic addition, nitro reduction and amide formation to afford twelve compounds ( 25~36) of 1-benzenesulfonyl-7-arylcarboxamido-7- 1H-indoles. The anti-proliferation of the modified compounds were evaluated in human oral epidermoid carcinoma cell. The most potent compound of 30 showed a IC50 of 0.06μM. Other three compounds of 27, 28 and 31 also showed a promising result and are active in anti-tumor activity.