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

Kandil, Sahar ORCID:, Balzarini, Jan, Rat, Stephanie, Brancale, Andrea ORCID:, Westwell, Andrew D. ORCID: and McGuigan, Christopher ORCID: 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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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

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