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

Sahar Kandil1, Jan Balzarini2, Stephanie Rat1

  • 1School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK.

Bioorganic & Medicinal Chemistry Letters
|November 8, 2016
PubMed

Insights

Novel ProTides demonstrated enhanced potency against leukemia and other cancer cells, offering a promising alternative to traditional nucleoside chemotherapy with minimal toxicity to healthy cells.

Area of Science:

  • Medicinal Chemistry
  • Cancer Therapeutics
  • Drug Discovery

Background:

  • Nucleosides are key cancer chemotherapeutics but face challenges with cellular uptake, activation, and breakdown.
  • ProTides (monophosphate pro-nucleotides) offer a strategy to overcome these limitations by bypassing cellular transport and kinase activation steps.

Purpose of the Study:

  • To structurally modify and evaluate BVdU ProTides for improved anticancer efficacy.
  • To assess the biological activity of novel phosphoramidates against various cancer cell lines.

Main Methods:

  • Synthesis of forty-six phosphoramidate derivatives of BVdU ProTides.
  • Biological evaluation against murine leukemia (L1210), human T-lymphocyte (CEM), and human cervical carcinoma (HeLa) cell lines.
  • Separation and characterization of diastereoisomeric mixtures.

Main Results:

  • Achieved up to twenty-fold increase in potency against L1210 cells compared to the parent BVdU.
  • Demonstrated low micromolar activity for several ProTides against CEM and HeLa cells, where BVdU was inactive.
  • Exhibited minimal toxicity towards non-tumourigenic human lung fibroblast cell cultures.

Conclusions:

  • Structural optimization of BVdU ProTides significantly enhances anticancer potency.
  • ProTides represent a viable strategy to overcome nucleoside limitations in cancer therapy.
  • The developed ProTides show selective toxicity towards cancer cells with a good safety profile.
Keywords:
AnticancerBVdUBrivudineNucleosidePhosphoramidateProTideProdrug

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