ProTides of BVdU as potential anticancer agents upon efficient intracellular delivery of their activated metabolites

Kandil, Sahar ORCID: https://orcid.org/0000-0003-1806-9623, Balzarini, Jan, Rat, Stephanie, Brancale, Andrea ORCID: https://orcid.org/0000-0002-9728-3419, Westwell, Andrew D. ORCID: https://orcid.org/0000-0002-5166-9236 and McGuigan, Christopher ORCID: https://orcid.org/0000-0001-8409-710X 2016. ProTides of BVdU as potential anticancer agents upon efficient intracellular delivery of their activated metabolites. Biorganic and Medicinal Chemistry Letters 26 (23) , pp. 5618-5623. 10.1016/j.bmcl.2016.10.077

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Abstract

Nucleosides represent a major chemotherapeutic class for treating cancer, however their limitations in terms of cellular uptake, nucleoside kinase-mediated activation and catabolism are well-documented. The monophosphate pro-nucleotides known as ProTides represents a powerful strategy for bypassing the dependence on active transport and nucleoside kinase-mediated activation. Herein, we report the structural tuning of BVdU ProTides. Forty six phosphoramidates were prepared and biologically evaluated against three different cancer cell lines; murine leukemia (L1210), human CD4 + T-lymphocyte (CEM) and human cervical carcinoma (HeLa). Twenty-fold potency enhancement compared to BVdU was achieved against L1210 cells. Interestingly, a number of ProTides showed low micromolar activity against CEM and HeLa cells compared to the inactive parent BVdU. The ProTides showed poor, if any measurable toxicity to non-tumourigenic human lung fibroblast cell cultures. Separation of four pairs of the diastereoisomeric mixtures and comparison of their spectral properties, biological activities and enzymatic activation rate is reported.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy
Subjects:	R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) R Medicine > RM Therapeutics. Pharmacology
Publisher:	Elsevier
ISSN:	0960-894X
Date of First Compliant Deposit:	25 November 2016
Date of Acceptance:	25 October 2016
Last Modified:	05 Jan 2024 06:01
URI:	https://orca.cardiff.ac.uk/id/eprint/96425

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