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Anchimerically Activated ProTides as Inhibitors of Cap-Dependent Translation and Inducers of Chemosensitization in Mantle Cell Lymphoma
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-09-20 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00916 Aniekan Okon , JingJing Han 1 , Surendra Dawadi , Christos Demosthenous 1 , Courtney C. Aldrich , Mamta Gupta 2 , Carston R. Wagner
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-09-20 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00916 Aniekan Okon , JingJing Han 1 , Surendra Dawadi , Christos Demosthenous 1 , Courtney C. Aldrich , Mamta Gupta 2 , Carston R. Wagner
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The cellular delivery of nucleotides through various pronucleotide strategies has expanded the utility of nucleosides as a therapeutic class. Although highly successful, the highly popular ProTide system relies on a four-step enzymatic and chemical process to liberate the corresponding monophosphate. To broaden the scope and reduce the number of steps required for monophosphate release, we have developed a strategy that depends on initial chemical activation by a sulfur atom of a methylthioalkyl protecting group, followed by enzymatic hydrolysis of the resulting phosphoramidate monoester. We have employed this ProTide strategy for intracellular delivery of a nucleotide antagonist of eIF4E in mantle cell lymphoma (MCL) cells. Furthermore, we demonstrated that chemical inhibition of cap-dependent translation results in suppression of c-Myc expression, increased p27 expression, and enhanced chemosensitization to doxorubicin, dexamethasone, and ibrutinib. In addition, the new ProTide strategy was shown to enhance oral bioavailability of the corresponding monoester phosphoramidate.
中文翻译：
端粒激活蛋白作为帽依赖翻译的抑制剂和地幔细胞淋巴瘤的化学增敏诱导剂。
通过各种前核苷酸策略的核苷酸细胞递送已经扩大了核苷作为治疗类的用途。尽管非常成功，但广受欢迎的ProTide系统依靠四步酶和化学过程来释放相应的单磷酸盐。为了扩大范围并减少单磷酸酯释放所需的步骤数，我们开发了一种策略，该策略取决于通过甲硫基烷基保护基团的硫原子进行的初始化学活化，然后对所得的氨基磷酸酯单酯进行酶促水解。我们已采用该ProTide策略在套细胞淋巴瘤（MCL）细胞中进行eIF4E核苷酸拮抗剂的细胞内递送。此外，我们证明了对帽依赖性翻译的化学抑制会导致c-Myc表达的抑制，p27表达的增加以及对阿霉素，地塞米松和依鲁替尼的化学增敏作用的增强。此外，新的ProTide策略已显示出可提高相应单酯氨基磷酸酯的口服生物利用度。
更新日期：2017-09-20
中文翻译：
端粒激活蛋白作为帽依赖翻译的抑制剂和地幔细胞淋巴瘤的化学增敏诱导剂。
通过各种前核苷酸策略的核苷酸细胞递送已经扩大了核苷作为治疗类的用途。尽管非常成功，但广受欢迎的ProTide系统依靠四步酶和化学过程来释放相应的单磷酸盐。为了扩大范围并减少单磷酸酯释放所需的步骤数，我们开发了一种策略，该策略取决于通过甲硫基烷基保护基团的硫原子进行的初始化学活化，然后对所得的氨基磷酸酯单酯进行酶促水解。我们已采用该ProTide策略在套细胞淋巴瘤（MCL）细胞中进行eIF4E核苷酸拮抗剂的细胞内递送。此外，我们证明了对帽依赖性翻译的化学抑制会导致c-Myc表达的抑制，p27表达的增加以及对阿霉素，地塞米松和依鲁替尼的化学增敏作用的增强。此外，新的ProTide策略已显示出可提高相应单酯氨基磷酸酯的口服生物利用度。
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