Chromophore-modified antitumor anthracenediones: synthesis, DNA binding, and cytotoxic activity of 1,4-bis[(aminoalkyl)amino]benzo[g]-phthalazine-5,10-diones.
Chromophore-modified antitumor anthracenediones: synthesis, DNA binding, and cytotoxic activity of 1,4-bis[(aminoalkyl)amino]benzo[g]-phthalazine-5,10-diones.
复制标题
DOI：
10.1021/jm00003a015
复制
发表时间：
1995-02
影响因子：
7.3
通讯作者：
C. Gandolfi;G. Beggiolin;E. Menta;M. Palumbo;C. Sissi;S. Spinelli;F. Johnson
中科院分区：
文献类型：
--
作者：
C. Gandolfi;G. Beggiolin;E. Menta;M. Palumbo;C. Sissi;S. Spinelli;F. Johnson
作为探索杂原子引入蒽-9，10-二酮发色团的影响的计划的一部分，我们合成了与抗肿瘤剂氨美蒽醌和米托蒽醌相关的新型1，4-双[（氨烷基）氨基]-苯并[g]酞嗪-5，10-二酮（BPDs）1。通过铬酸氧化酰化苯并[g]酞嗪5，然后酸水解或通过甲硅烷基化-胺化5，10-二羟基苯并[g]酞嗪-1，4-二酮（8）制备衍生物1。1-[（氨烷基）氨基]-4-氨基同系物2是从5的氧化中以低收率分离出来的副产物。针对一组人肿瘤细胞系，苯并[g]酞嗪-5，10-二酮1和2显示出与米托蒽醌相当或甚至上级的细胞毒活性。在化合物1中，出现不同于在碳环系列中操作的结构-活性关系。DNA结合的研究与ametantron-like化合物1c和它的单臂同系物2c表明，2，3-二氮杂亚基的蒽-9，10-二酮生色团的引入降低了DNA的药物的亲和力相比，ametantrone。另一方面，侧链基团的数量在很大程度上不影响结合。这些发现似乎表明细胞死亡的机制，而不是由简单的相互作用的1，4-BPD 1和2与DNA诱导。
As part of a program aimed at exploring the effect of the introduction of heteroatoms into the anthracene-9,10-dione chromophore, we have synthesized novel 1,4-bis[(aminoalkyl)amino]-benzo[g]phthalazine-5,10-diones (BPDs) 1 which are related to the antitumor agents ametantrone and mitoxantrone. Derivatives 1 were prepared by chromic acid oxidation of acylated benzo[g]phthalazines 5 followed by acid hydrolysis or by silylation-amination of 5,10-dihydroxybenzo[g]phthalazine-1,4-dione (8). The 1-[(aminoalkyl)amino]-4-amino congeners 2 were isolated in low yields as byproducts from the oxidation of 5. Against a panel of human tumor cell lines, the benzo[g]phthalazine-5,10-diones 1 and 2 exhibited cytotoxic activity comparable or even superior to that of mitoxantrone. In compounds 1, structure-activity relationships different than those operative in the carbocyclic series appeared to emerge. DNA-binding studies with the ametantrone-like compound 1c and its single-armed congener 2c indicated that the introduction of a 2,3-diaza subunit into the anthracene-9,10-dione chromophore reduces the affinity of the drug for DNA in comparison with ametantrone. On the other hand, the number of side-chain groups does not affect binding to a great extent. These findings seem to suggest mechanisms of cell death other than those induced by simple interaction of the 1,4-BPDs 1 and 2 with DNA.