Tumor-Targeted Delivery of 6-Diazo-5-oxo-L-norleucine (DON) Using Substituted Acetylated Lysine Prodrugs
Tumor-Targeted Delivery of 6-Diazo-5-oxo-L-norleucine (DON) Using Substituted Acetylated Lysine Prodrugs
复制标题
DOI：
10.1021/acs.jmedchem.8b02009
复制
发表时间：
2019-04-11
影响因子：
7.3
通讯作者：
Slusher, Barbara S.
中科院分区：
文献类型：
--
作者：
Tenora, Lukas;Alt, Jesse;Slusher, Barbara S.
6-重氮-5-氧代-L-正亮氨酸（DON）是一种具有强大抗癌功效的谷氨酰胺拮抗剂;然而，其治疗潜力受到其生物分布和对正常组织（特别是胃肠道（GI）组织）的毒性的阻碍。为了规避DON的毒性，我们合成了一系列肿瘤靶向DON前药，这些前药被设计成在血浆中惰性循环并且在肿瘤中优先激活DON。我们最好的前药6（2-（6-乙酰氨基-2-（金刚烷-1-甲酰胺基）己酰胺基）-6-重氮基-5-氧代己酸异丙酯）在血浆、肝脏和肠匀浆中显示出稳定性，但在P493 B淋巴瘤细胞中容易裂解为DON，表现出相对于DON的55倍增强的肿瘤细胞-血浆比，并导致细胞增殖的剂量依赖性抑制。使用显示出模拟人前药代谢的羧酸酯酶1敲除小鼠，全身施用6递送比GI组织（毒性组织; AUC（0-t）= 0.45 nmol h/g）高11倍的DON暴露于肿瘤（靶组织; AUC（0-t）= 5.1 nmol h/g）。总之，这些研究描述了发现提供选择性肿瘤暴露的谷氨酰胺拮抗剂前药。
6-Diazo-5-oxo-L-norleucine (DON) is a glutamine antagonist with robust anticancer efficacy; however, its therapeutic potential was hampered by its biodistribution and toxicity to normal tissues, specifically gastrointestinal (GI) tissues. To circumvent DON's toxicity, we synthesized a series of tumor-targeted DON prodrugs designed to circulate inert in plasma and preferentially activate over DON in tumor. Our best prodrug 6 (isopropyl 2-(6-acetamido-2-(adamantane-1-carboxamido)hexanamido)-6-diazo-5-oxohexanoate) showed stability in plasma, liver, and intestinal homogenates yet was readily cleaved to DON in P493B lymphoma cells, exhibiting a 55-fold enhanced tumor cell-to-plasma ratio versus that of DON and resulting in a dose-dependent inhibition of cell proliferation. Using carboxylesterase 1 knockout mice that were shown to mimic human prodrug metabolism, systemic administration of 6 delivered 11-fold higher DON exposure to tumor (target tissue; AUC(0-t) = 5.1 nmol h/g) versus GI tissues (toxicity tissue; AUC(0-t) = 0.45 nmol h/g). In summary, these studies describe the discovery of a glutamine antagonist prodrug that provides selective tumor exposure.