Slusarczyk et al._Single diastereomers_Revision_03052021.pdf (1.45 MB)
Single Diastereomers of the Clinical Anticancer ProTide Agents NUC-1031 and NUC-3373 Preferentially Target Cancer Stem Cells In Vitro
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posted on 2023-06-10, 00:21 authored by Magdalena Slusarczyk, Michaela Serpi, Essam Ghazaly, Benson M Kariuki, Christopher McGuigan, Christopher PepperChristopher PepperA 3'-protected route toward the synthesis of the diastereomers of clinically active ProTides, NUC-1031 and NUC-3373, is described. The in vitro cytotoxic activities of the individual diastereomers were found to be similar to their diastereomeric mixtures. In the KG1a cell line, NUC-1031 and NUC-3373 have preferential cytotoxic effects on leukemic stem cells (LSCs). These effects were not diastereomer-specific and were not observed with the parental nucleoside analogues gemcitabine and FUDR, respectively. In addition, NUC-1031 preferentially targeted LSCs in primary AML samples and cancer stem cells in the prostate cancer cell line, LNCaP. Although the mechanism for this remains incompletely resolved, NUC-1031-treated cells showed increased levels of triphosphate in both LSC and bulk tumor fractions. As ProTides are not dependent on nucleoside transporters, it seems possible that the LSC targeting observed with ProTides may be caused, at least in part, by preferential accumulation of metabolized nucleos(t)ide analogues.
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Publication status
- Published
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- Accepted version
Journal
Journal of Medicinal ChemistryISSN
0022-2623Publisher
American Chemical SocietyExternal DOI
Issue
12Volume
64Page range
8179-8193Department affiliated with
- BSMS Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2021-07-15First Open Access (FOA) Date
2022-06-05First Compliant Deposit (FCD) Date
2021-07-14Usage metrics
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