Antitumor agents .167. Synthesis and structure-activity correlations of the cytotoxic anthraquinone 1,4-bis-(2,3-epoxypropylamino)-9,10-anthracenedione, and of related compounds
Antitumor agents .167. Synthesis and structure-activity correlations of the cytotoxic anthraquinone 1,4-bis-(2,3-epoxypropylamino)-9,10-anthracenedione, and of related compounds
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DOI：
10.1016/s0968-0896(97)00097-7
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发表时间：
1997-08-01
影响因子：
3.5
通讯作者：
Lee, KH
中科院分区：
文献类型：
--
作者：
Johnson, MG;Kiyokawa, H;Lee, KH
本实验室合成了1,4-双-(2,3-环氧丙氨基)-9,10-蒽二酮(3)，并被发现是一种专利抗肿瘤药物。还制备了该化合物含有蒽醌、萘醌和醌骨架的衍生物，并评估了几种细胞系的体外细胞毒活性。这些分子被设计为双功能抗肿瘤剂，具有以下潜力：（1）由于其平面主链而充当嵌入剂；以及（2）由于其侧链中存在烷基化部分而充当烷基化剂。具有蒽醌骨架和含有环氧化物或卤代醇作为烷基化物质的丙氨基侧链的化合物比具有萘醌或醌骨架的类似化合物显示出更高的活性。没有这些烷基化官能团（例如，具有烯烃或氨基）的化合物通常是无活性的。平面骨架上的羟基取代与烷基化侧链结合使化合物具有最有效的细胞毒性活性。羟基和侧链的位置可以改变，而不会显着影响活性。当环氧丙氧基侧链取代母体化合物中的环氧丙氨基侧链时，活性得以保留。 (C) 1997 爱思唯尔科学有限公司。
1,4-Bis-(2,3-epoxypropylamino)-9,10-anthracenedione (3) was synthesized in this laboratory and was found to be a patent antitumor agent. Derivatives of this compound containing anthraquinone, naphthoquinone, and quinone skeletons were also prepared and evaluated for in vitro cytotoxic activity in several cell lines. These molecules were designed as bifunctional antitumor agents with the potential to act as (1) intercalating agents due to their planar backbones, and (2) alkylating agents due to the presence of alkylating moieties in their side chains. Compounds with an anthraquinone skeleton and propylamino side chains containing epoxides or halohydrins as the alkylating species showed greater activity than similar compounds with naphthoquinone or quinone skeletons. Compounds without these alkylating functionalities (e.g., with alkene or amino groups) were generally inactive. Hydroxy substitution on the planar skeleton in conjunction with alkylating side chains gave compounds with the most potent cytotoxic activity. The position of the hydroxy groups and side chains could be varied without substantially affecting activity. Activity was retained when an epoxypropyloxy side chain was substituted for the epoxypropylamino side chain in the parent compound. (C) 1997 Elsevier Science Ltd.