Discovery of 6-Diazo-5-oxo-L-norleucine (DON) Prodrugs with Enhanced CSF Delivery in Monkeys: A Potential Treatment for Glioblastoma
Discovery of 6-Diazo-5-oxo-L-norleucine (DON) Prodrugs with Enhanced CSF Delivery in Monkeys: A Potential Treatment for Glioblastoma
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DOI：
10.1021/acs.jmedchem.6b01069
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发表时间：
2016-09-22
影响因子：
7.3
通讯作者：
Slusher, Barbara S.
中科院分区：
文献类型：
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作者：
Rais, Rana;Jancarik, Andrej;Slusher, Barbara S.
谷氨酰胺拮抗剂6-重氮-5-氧代-1-正亮氨酸（DON，1）在临床前和临床研究中显示出强大的抗癌功效，但由于显著的全身毒性，其开发被停止。在此，我们证明DON抑制谷氨酰胺代谢，并在胶质母细胞瘤小鼠模型中提供抗肿瘤功效，尽管观察到毒性。为了提高DON的治疗指数，我们利用前药策略来增加其脑递送并限制全身暴露。出乎意料的是，简单的基于烷基酯的前药由于化学不稳定性而无效，环化形成独特的重氮亚胺。然而，掩蔽DON的胺和羧酸酯官能团赋予生物测试足够的化学稳定性。虽然这些双部分前药在小鼠血浆中表现出快速代谢，但一些在猴和人血浆中提供了优异的稳定性。在猴中评价了最稳定的化合物（5c，甲基-POM-DON-异丙基酯），其中其相对于DON实现了10倍增强的脑脊液与血浆比率。这种策略可能为多形性胶质母细胞瘤患者提供一种DON利用的途径。
The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON, 1) has shown robust anticancer efficacy in preclinical and clinical studies, but its development was halted due to marked systemic toxicities. Herein we demonstrate that DON inhibits glutamine metabolism and provides antitumor efficacy in a murine model of glioblastoma, although toxicity was observed. To enhance DONs therapeutic index, we utilized a prodrug strategy to increase its brain delivery and limit systemic exposure. Unexpectedly, simple alkyl ester-based prodrugs were ineffective due to chemical instability cyclizing to form a unique diazo-imine. However, masking both DONs amine and carboxylate functionalities imparted sufficient chemical stability for biological testing. While these dual moiety prodrugs exhibited rapid metabolism in mouse plasma, several provided excellent stability in monkey and human plasma. The most stable compound (5c, methyl-POM-DON-isopropyl-ester) was evaluated in monkeys, where it achieved 10-fold enhanced cerebrospinal fluid to plasma ratio versus DON. This strategy may provide a path to DON utilization in glioblastoma multiforme patients.