Protease-mediated fragmentation of p-amidobenzyl ethers: a new strategy for the activation of anticancer prodrugs.
Protease-mediated fragmentation of p-amidobenzyl ethers: a new strategy for the activation of anticancer prodrugs.
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DOI：
10.1021/jo016187
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发表时间：
2002-02
期刊：
影响因子：
--
通讯作者：
B. Toki;C. Cerveny;A. Wahl;P. Senter
中科院分区：
文献类型：
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作者：
B. Toki;C. Cerveny;A. Wahl;P. Senter
描述了一种基于对氨基苄基醚的 1,6-消除反应的新的抗癌前药激活策略。使用 N-保护肽苯甲氧基羰基-缬氨酸-瓜氨酸 (Z-val-cit) 进行模型研究，该肽连接到 1-萘酚和 N-乙酰去甲麻黄碱的对氨基苯甲基醚衍生物的氨基上。形成的酰胺键旨在被组织蛋白酶 B 水解，组织蛋白酶 B 是一种与快速生长和转移性癌相关的蛋白酶。用酶处理后，1-萘酚 (2) 的 Z-val-cit-p-amidobenzyl 醚发生肽键水解，并快速释放 1-萘酚。 N-乙酰去甲麻黄碱的脂肪族 Z-val-cit-p-酰胺基苄基醚 (5) 也经历了酰胺键水解，但没有随后消除 N-乙酰去甲麻黄碱。基于这些结果，酚类抗癌药物依托泊苷（6）和考布他汀A-4（7）通过醚键与Z-val-cit-p-酰胺基苯甲醇连接，分别形成肽药物衍生物8和9。两种化合物在水性缓冲液和血清中均稳定，并在用组织蛋白酶 B 处理后发生醚裂解，导致母体药物以未化学修饰的形式释放。所释放的药物在一组癌细胞系上的效力比前药前体强 13-50 倍。相比之下，考布他汀 A-4 的相应碳酸酯衍生物 (13) 在水性环境中不稳定，并且与考布他汀 A-4 具有相同的细胞毒性。这一结果扩展了自毁对氨基苄基在芳香醚裂解中的用途，并为抗癌前药的开发提供了新的策略。
A new anticancer prodrug activation strategy based on the 1,6-elimination reaction of p-aminobenzyl ethers is described. Model studies were undertaken with the N-protected peptide benzyloxycarbonyl-valine-citrulline (Z-val-cit), which was attached to the amino groups of p-aminobenzyl ether derivatives of 1-naphthol and N-acetylnorephedrine. The amide bond that formed was designed for hydrolysis by cathepsin B, a protease associated with rapidly growing and metastatic carcinomas. Upon treatment with the enzyme, the Z-val-cit-p-amidobenzyl ether of 1-naphthol (2) underwent peptide bond hydrolysis with the rapid release of 1-naphthol. The aliphatic Z-val-cit-p-amidobenzyl ether of N-acetylnorephedrine (5) also underwent amide bond hydrolysis, but without the ensuing elimination of N-acetylnorephedrine. On the basis of these results, the phenolic anticancer drugs etoposide (6) and combretastatin A-4 (7) were attached to the Z-val-cit-p-amidobenzyl alcohol through ether linkages, forming the peptide-drug derivatives 8 and 9, respectively. Both compounds were stable in aqueous buffers and serum and underwent ether fragmentation upon treatment with cathepsin B, resulting in the release of the parent drugs in chemically unmodified forms. The released drugs were 13-50 times more potent than were the prodrug precursors on a panel of cancer cell lines. In contrast, the corresponding carbonate derivative of combretastatin A-4 (13) was unstable in aqueous environments and was as cytotoxic as combretastatin A-4. This result extends the use of the self-immolative p-aminobenzyl group for the fragmentation of aromatic ethers and provides a new strategy for anticancer prodrug development.