Bioreduction activated prodrugs of camptothecin: molecular design, synthesis, activation mechanism and hypoxia selective cytotoxicity
Bioreduction activated prodrugs of camptothecin: molecular design, synthesis, activation mechanism and hypoxia selective cytotoxicity
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DOI：
10.1039/b502813b
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发表时间：
2005-01-01
影响因子：
3.2
通讯作者：
Nishimoto, S
中科院分区：
文献类型：
--
作者：
Zhang, Z;Tanabe, K;Nishimoto, S
合成了几种喜树碱（CPT）的水溶性衍生物（CPT 3，CPT 3a-d），其中CPT 3带有N，N '-二甲基-1-氨基乙基氨基甲酸酯侧链，并进一步与吲哚醌、4-硝基苄醇和4-硝基呋喃醇的结构单元进行还原消除偶联，合成了喜树碱的新型前药（CPT 4 -6）。所有CPT衍生物的细胞毒性均低于其母体化合物CPT。CPT 4和CPT 6对肿瘤细胞的细胞毒作用具有更高的缺氧选择性。还讨论了在DT-心肌黄酶存在下，代表性前药CPT 4被激活以释放CPT的机制。生物还原活化的CPT前体药物CPT 4和CPT 6有望应用于缺氧靶向的肿瘤化疗。
Several water- soluble derivatives (CPT3, CPT3a-d) of camptothecin (CPT) were synthesized, among which CPT3 bearing an N, N '-dimethyl-1-aminoethylcarbamate side- chain was further conjugated with reductively eliminating structural units of indolequinone, 4-nitrobenzyl alcohol and 4- nitrofuryl alcohol to produce novel prodrugs of camptothecin (CPT4-6). All CPT derivatives were of lower cytotoxicity than their parent compound of CPT. In contrast, CPT4 and CPT6 showed higher hypoxia selectivity of cytotoxicity towards tumor cells than CPT. A mechanism by which a representative prodrug CPT4 is activated in the presence of DT- diaphorase to release CPT was also discussed. The bioreduction activated CPT prodrugs including CPT4 and CPT6 are identified to be promising for application to the hypoxia targeting tumor chemotherapy.