Single diastereomers of the clinical anticancer ProTide agents NUC-1031 and NUC-3373 preferentially target cancer stem cells in vitro

Slusarczyk, Magdalena ORCID: https://orcid.org/0000-0002-4707-7190, Serpi, Michaela ORCID: https://orcid.org/0000-0002-6162-7910, Ghazaly, Essam, Kariuki, Benson M. ORCID: https://orcid.org/0000-0002-8658-3897, McGuigan, Christopher ORCID: https://orcid.org/0000-0001-8409-710X and Pepper, Chris 2021. Single diastereomers of the clinical anticancer ProTide agents NUC-1031 and NUC-3373 preferentially target cancer stem cells in vitro. Journal of Medicinal Chemistry 64 (12) , pp. 8179-8193. 10.1021/acs.jmedchem.0c02194

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy Chemistry
Publisher:	American Chemical Society
ISSN:	0022-2623
Date of First Compliant Deposit:	23 June 2021
Date of Acceptance:	24 May 2021
Last Modified:	13 Nov 2024 13:30
URI:	https://orca.cardiff.ac.uk/id/eprint/142153

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