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.
Highlights
Nucleosides represent a major chemotherapeutic class for treating cancer, 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
A number of ProTides showed low micromolar activity against CEM and human cervical carcinoma (HeLa) cells compared to the inactive parent BVdU
Summary
Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl. As ProTides, pioneered by McGuigan and co-workers, has been proven to enhance the activity of parent nucleosides by improving intracellular transport and/or by bypassing the rate-limiting monophosphorylation step. The application of ProTide technology on the BVdU scaffold led to less potent derivatives compared to the parent agent against VZV in cell culture models [6].
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