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

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colon 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。

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

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

  2. 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 proliferation 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.

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