Anchimerically Activated ProTides as Inhibitors of Cap-Dependent Translation and Inducers of Chemosensitization in Mantle Cell Lymphoma

Aniekan Okon, Jingjing Han, Surendra Dawadi, Christos Demosthenous, Courtney C. Aldrich, Mamta Gupta, Carston R. Wagner

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)8131-8144
Number of pages14
JournalJournal of medicinal chemistry
Volume60
Issue number19
DOIs
StatePublished - Oct 12 2017

Bibliographical note

Funding Information:
We thank Xun Ming for his technical expertise with the LC−MS/ MS analyses. This work is supported by ASH Bridge Grant Award from American Society of Hematology and the University of Minnesota Foundation. This work is also supported in part through startup package from George Washington University. Mass spectrometry was carried out with the assistance of Dr. Bruce A. Witthuhn in the Analytical Biochemistry Shared Resource of the Masonic Cancer Center, University of Minnesota, funded in part by Cancer Center Support Grant CA-77598. We also gratefully acknowledge financial support from the National Institutes of Health Grant AI070219 (to C.C.A.).

Publisher Copyright:
© 2017 American Chemical Society.

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