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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 Pepper
A 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.

History

Publication status

  • Published

File Version

  • Accepted version

Journal

Journal of Medicinal Chemistry

ISSN

0022-2623

Publisher

American Chemical Society

Issue

12

Volume

64

Page range

8179-8193

Department affiliated with

  • BSMS Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2021-07-15

First Open Access (FOA) Date

2022-06-05

First Compliant Deposit (FCD) Date

2021-07-14

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