Design and optimization of 20-O-linked camptothecin glycoconjugates as anticancer agents
Design and optimization of 20-O-linked camptothecin glycoconjugates as anticancer agents
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DOI：
10.1021/jm010893l
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发表时间：
2001-11-22
影响因子：
7.3
通讯作者：
Fiebig, HH
中科院分区：
文献类型：
--
作者：
Lerchen, HG;Baumgarten, J;Fiebig, HH
为了改善20（S）-喜树碱的生物学特性，已经设计了一类新型的20-O-连接的喜树碱糖缀合物，其通过主动转运机制优先被细胞摄取到肿瘤细胞中。这种缀合物已被优化用于增强的溶解度、喜树碱内酯环的稳定性、足够的水解和蛋白水解稳定性以及肿瘤选择性的总体改善。肽间隔基的组成对缀合物的体外和体内稳定性和生物活性具有主要影响，在与喜树碱的连接位置处具有缬氨酸残基的糖缀合物17-22足够稳定，并且对HT 29和其他肿瘤细胞系显示出良好的体外抗肿瘤活性。荧光显微镜和流式细胞术实验表明，糖缀合物如19通过主动转运机制被摄取到肿瘤细胞系HT 29的溶酶体隔室中。与喜树碱部分连接的特定氨基酸残基的空间构型对乳腺癌异种移植物MX-1模型中相应糖缀合物的体内活性具有主要影响。抑制肿瘤生长> 96%，糖缀合物19和21在该特定模型中显示出最好的活性，并且已经被更广泛地研究。在对造血干细胞和肝细胞的毒性方面，糖缀合物19与托泊替康4和糖缀合物21相比是有利的。根据其概况，已选择19个进行临床试验。
To improve the biological profile of 20(S)-camptothecin, a novel class of 20-O-linked camptothecin glycoconjugates has been designed for preferential cellular uptake into tumor cells by an active transport mechanism. Such conjugates have been optimized for enhanced solubility, stabilization of the camptothecin lactone ring, sufficient hydrolytic and proteolytic stability, and for an overall improvement in tumor selectivity. The constitution of the peptide spacer has a major impact on stability and biological activity of the conjugates both in vitro and in vivo, Glycoconjugates 17-22 with valine residues at the linkage position to camptothecin are sufficiently stable and show good antitumor activity in vitro against HT29 and other tumor cell lines. Fluorescence microscopy and flow cytometry experiments indicate that glycoconjugates such as 19 are taken up into lysosomal compartments of the tumor cell line HT29 by an active transport mechanism. The steric configuration of the particular amino acid residues linked to the camptothecin moiety has a major impact on the in vivo activity of the corresponding glycoconjugates in the breast cancer xenograft MX-1 model. Inhibiting tumor growth by > 96%, the glycoconjugates 19 and 21 show the best activity in this particular model and have been investigated more extensively. The glycoconjugate 19 compares favorably to topotecan 4 and glycoconjugate 21 with respect to toxicity against hematopoietic stem cells and hepatocytes. Based on its profile, 19 has been selected for clinical trials.