Isomer-dependent daunomycin release and in vitro antitumour effect of cis-aconityl-daunomycin
Isomer-dependent daunomycin release and in vitro antitumour effect of cis-aconityl-daunomycin
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DOI：
10.1016/s0006-291x(03)00394-2
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发表时间：
2003-04-04
影响因子：
3.1
通讯作者：
Hudecz, F
中科院分区：
文献类型：
--
作者：
Reményi, J;Balázs, B;Hudecz, F
通过柔红霉素与顺式乌头酸酐的反应，分离得到顺式柔红霉素(CAD)的两个异构体。异构体的结构经MS、H-1和C-13核磁共振实验确证。与前面的假设相反，我们的结果表明，这两个异构体分别属于顺式和反式顺乌头基柔红霉素单酰胺的异构体。我们发现这两种异构体对柔红霉素的释放具有不同的pH依赖性。异构体对c26结肠癌和mda-MB 435p人乳腺癌细胞的体外抗肿瘤作用的比较分析表明，CAD-1比CAD-2更有效，但差异的程度取决于肿瘤细胞。这项研究的结果可以通过使用不稳定酸的间隔物来设计和制备药物的蛋白质/肽连接物来理解，因为这表明异构体可能具有明显不同的生物活性。(C)2003年埃尔塞维尔科学公司(美国)。版权所有。
Two isomers of cis-aconytil-daunomycin (cAD) were isolated after the reaction of daunomycin with cis-aconitic-anhydride. The structure of the isomers was identified by MS-spectroscopy and H-1 and C-13 NMR experiments. In contrast with the assumptions described earlier, our results show that the two isomers belong to the cis- and trans-isomers of the alpha-monoamide of cis-aconityldaunomycin, respectively. We found that the pH dependent daunomycin release is different for the two isomers. Comparative analysis of the in vitro antitumour effect of the isomers on c26 colon carcinoma and on MDA-MB 435P human breast carcinoma cell lines showed that cAD-1 is more potent than cAD-2, but the extent of differences is tumour cell dependent. The results of this study might be appreciated in the light of the use of acid-labile spacer for the design and preparation of protein/peptide conjugates of drugs by indicating that isomers could possess markedly different biological activity. (C) 2003 Elsevier Science (USA). All rights reserved.