Huang Hsu-Shan, Chiu Hui-Fen, Lee An-Long, Guo Ching-Long, Yuan Chun-Lung
School of Pharmacy, National Defense Medical Center, PO Box 90048-508, Neihu 114 Taipei, Taiwan, ROC.
Bioorg Med Chem. 2004 Dec 1;12(23):6163-70. doi: 10.1016/j.bmc.2004.09.001.
Anthraquinone-based compounds are attractive target for the design of new anticancer drugs. We have previously described a series of 1,5- and 1,4-difunctionalized anthraquinones, which exhibit different spectra of potency, together with human telomerase evaluation. The present study details the preparation of further, distinct series of regioisomeric difunctionalized amidoanthraquinone and examines their in vitro cytotoxicity in C6, Hepa G2, and 2.2.15 cell lines. Two structurally related compounds, mitoxantrone and adriamycin, were tested in parallel as positive controls. The structure-activity relationships indicated amido substitution may lead to a different mechanism of cytotoxicity. Compounds, which have -(CH2)n- side chains terminating in basic groups such as aminoalkyl-substituted, showed cytotoxic activity in several cell lines. The exact mode of intercalative binding may be dictated by the positional placement of substituent side chains. Implications for amidoanthraquinone cytotoxicity as potential anticancer agents are discussed. In addition, we further delineate the nature of the pharmacophore for this class of compounds, which provides a rational basis for the structure-activity relationships.
基于蒽醌的化合物是新型抗癌药物设计的有吸引力的靶点。我们之前描述过一系列1,5 -和1,4 -二官能化蒽醌，它们表现出不同的效价谱，并对人端粒酶进行了评估。本研究详细介绍了另外一系列不同的区域异构体二官能化酰胺蒽醌的制备，并检测了它们在C6、Hepa G2和2.2.15细胞系中的体外细胞毒性。两种结构相关的化合物米托蒽醌和阿霉素作为阳性对照同时进行测试。构效关系表明酰胺取代可能导致不同的细胞毒性机制。具有以碱性基团如氨基烷基取代结尾的-(CH2)n-侧链的化合物在几种细胞系中显示出细胞毒性活性。插入结合的确切模式可能由取代侧链的位置决定。讨论了酰胺蒽醌作为潜在抗癌剂的细胞毒性的意义。此外，我们进一步阐明了这类化合物药效团的性质，这为构效关系提供了合理的基础。
