5-amino-1-(chloromethyl)-1,2 dihydro-3H-benz [e]indoles:: Relationships between structure and cytotoxicity for analogues bearing different DNA minor groove binding subunits
5-amino-1-(chloromethyl)-1,2 dihydro-3H-benz [e]indoles:: Relationships between structure and cytotoxicity for analogues bearing different DNA minor groove binding subunits
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DOI：
10.1021/jm990136b
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发表时间：
1999-08-26
影响因子：
7.3
通讯作者：
Denny, WA
中科院分区：
文献类型：
--
作者：
Atwell, GJ;Milbank, JJB;Denny, WA
制备了一系列 5-氨基-seco-CBI 化合物，设计用作前药效应物，用于研究侧链类似物细胞毒性的构效关系。通过将 1-(氯甲基)-5-硝基-1,2-二氢-3H-苯并[e]吲哚与适当的羧酸偶联，然后硝基还原，或通过将适当的 5-氨基保护的二氢吲哚与 α,β-不饱和酸偶联，然后解封闭来制备化合物。在一系列肿瘤细胞系（AA8、UV4、EMT6、SKOV3）中评估了这些 AT 特异性 DNA 烷化剂的细胞毒性。对于带有吲哚羰基侧链的类似物，5'-甲氧基衍生物的细胞毒性最强（AA8 细胞中的 IC50 为 1.3 nM，暴露 4 小时），与母体 CBI-TMI（5',6',7'-三甲氧基吲哚）衍生物（上述测定中的 IC50 为 0.46 nM）相当。带有 O(CH2)(2)NMe2 取代基的溶解衍生物的子集的效力大约低 10 倍。对于侧链中含有丙烯酰接头的化合物，4'-甲氧基肉桂酰衍生物被证明是最具细胞毒性的（在上述测定中IC50为0.09 nM）。许多这些 5-氨基-seco-CBI-TMI 类似物（包括溶解的化合物）既可以作为细胞毒素，也可以作为设计用于肿瘤特异性激活的胺基前药的成分。
A series of 5-amino-seco-CBI compounds, designed for use as effecters for prodrugs, were prepared to study structure-activity relationships for the cytotoxicity of side chain analogues. Compounds were prepared by coupling 1-(chloromethyl)-5-nitro-1,2-dihydro-3H-benz[e]indole to appropriate carboxylic acids, followed by nitro group reduction, or by coupling suitable 5-amino-protected indolines to alpha,beta-unsaturated acids, followed by deblocking. These AT-specific DNA alkylating agents were evaluated for cytotoxicity in a series of tumor cell lines (AA8, UV4, EMT6, SKOV3). For those analogues bearing an indolecarbonyl side chain, the 5'-methoxy derivative was the most cytotoxic (IC50 1.3 nM in AA8 cells, 4 h exposure), comparable to that of the parent CBI-TMI (5',6',7'-trimethoxyindole) derivative (IC50 0.46 nM in the above assay). A subset of solubilized derivatives bearing O(CH2)(2)NMe2 substituents were about 10-fold less potent. For compounds containing an acryloyl linker in the side chain, the 4'-methoxycinnamoyl derivative proved the most cytotoxic (IC50 0.09 nM in the above assay). A number of these 5-amino-seco-CBI-TMI analogues (including the solubilized compounds) are of interest both as cytotoxins and as components of amine-based prodrugs designed for tumor-specific activation.