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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:26

Article

Kandil, Sahar¹  Balzarini, Jan²  Rat, Stephanie¹  Brancale, Andrea¹  Westwell, Andrew D.¹  McGuigan, Christopher¹ 

[1] Cardiff Univ, Sch Pharm & Pharmaceut Sci, King Edward VII Ave, Cardiff CF10 3NB, S Glam, Wales

[2] Katholieke Univ Leuven, Rega Inst Med Res, Minderbroedersstr 10, B-3000 Leuven, Belgium

关键词: BVdU;    ProTide;    Phosphoramidate;    Anticancer;    Nucleoside;    Prodrug;    Brivudine;   

DOI  :  10.1016/j.bmcl.2016.10.077

来源: Elsevier

【 摘 要 】

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. (C) 2016 The Authors. Published by Elsevier Ltd.

【 授权许可】

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