Synthesis and biological evaluation of 2′-carbamate-linked and 2′-carbonate-linked prodrugs of paclitaxel:: Selective activation by the tumor-associated protease plasmin
Synthesis and biological evaluation of 2′-carbamate-linked and 2′-carbonate-linked prodrugs of paclitaxel:: Selective activation by the tumor-associated protease plasmin
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DOI：
10.1021/jm0009078
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发表时间：
2000-08-10
影响因子：
7.3
通讯作者：
Scheeren, HW
中科院分区：
文献类型：
--
作者：
de Groot, FMH;van Berkom, LWA;Scheeren, HW
合成了无毒的紫杉醇-2′-氨基甲酸酯前药2-5和紫杉醇-2′-碳酸前药6，并进行了肿瘤相关酶纤溶酶活化试验。建立了一种合成paditaxel-2′-氨基甲酸酯的通用方法。在缓冲溶液中，含有未取代的乙二胺间隔剂的前药2不稳定，而前药3-6则高度稳定。前药3-6对7种人类肿瘤细胞系的细胞毒性比原药平均降低8000倍以上。前药5和前药6是目前报道的紫杉醇中最无毒的经选择性活化产生游离母药的前药。前药5和6在人纤溶酶存在下孵育，测定酶水解率和间隔物消除率。根据这些结果，前药6被选为有希望进行进一步体内研究的前药。
The nontoxic paclitaxel-2'-carbamate prodrugs 2-5 and paclitaxel-2'-carbonate prodrug 6 were synthesized and tested for activation by the tumor-associated enzyme plasmin. A generally applicable method for the synthesis of paditaxel-2'-carbamates was developed. In buffer solution, prodrug 2, which contained an unsubstituted ethylenediamine spacer, was not stable, whereas prodrugs 3-6 were highly stable. Prodrugs 3-6 showed on average a decrease in cytotoxicity of more than 8000-fold in comparison with the parent drug in seven human tumor cell lines. Prodrugs 5 and 6 are the most nontoxic prodrugs of paclitaxel that yield the free parent drug upon selective activation currently reported. Enzyme hydrolysis and spacer elimination rates were determined by incubation of prodrugs 5 and 6 in the presence of human plasmin. From these results, prodrug 6 was selected as the promising prodrug for further in vivo studies.