N-succinyl-(β-alanyl-L-leucyl-L-alanyl-L-leucyl)doxorubicin:: An extracellularly tumor-activated prodrug devoid of intravenous acute toxicity
N-succinyl-(β-alanyl-L-leucyl-L-alanyl-L-leucyl)doxorubicin:: An extracellularly tumor-activated prodrug devoid of intravenous acute toxicity
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DOI：
10.1021/jm0108754
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发表时间：
2001-10-25
影响因子：
7.3
通讯作者：
Trouet, A
中科院分区：
文献类型：
--
作者：
Fernandez, AM;Van Derpoorten, K;Trouet, A
静脉内施用N-（β-丙氨酰-L-亮氨酰-L-丙氨酰-L-亮氨酰）多柔比星（4）诱导急性毒性反应，在几分钟内杀死动物。这是由于其在生理pH下的正电荷以及其在水溶液中形成大聚集体的倾向。4的带负电荷的N-封端形式如琥珀酰基衍生物5可以通过静脉途径以超过多柔比星LD 50的10倍给药，而不诱导急性毒性反应，并且它们在体内是有活性的。
Intravenous administration of N-(beta -alanyl-L-leucyl-L-alanyl-L-leucyl)doxorubicin (4) induces an acute toxic reaction, killing animals in a few minutes. This results from its positive charge at physiological pH combined with its propensity to form large aggregates in aqueous solutions. Negatively charged N-capped versions of 4 such as the succinyl derivative 5 can be administered by the iv route at more than 10 times the LD50 of doxorubicin without inducing the acute toxic reaction, and they are active in vivo.