AI Article Synopsis
- Phosphonate and phosphate prodrugs are important for improving drug absorption, but their toxic metabolites pose risks that must be addressed.
- The study specifically looks at how certain metabolite compounds affect pancreatic cancer cells, glioblastoma cells, and mouse astrocytes, finding that 2-naphthol is particularly toxic to these cell types.
- A clear trend shows that normal cells are generally more vulnerable to the toxic effects of these prodrug metabolites compared to cancer cells, highlighting the need to consider this toxicity during drug development.
Article Abstract
Phosphonate and phosphate prodrugs are integral to enhancing drug permeability, but the potential toxicity of their metabolites requires careful consideration. This study evaluates the impact of widely used phosphoramidate, bis-amidate, and cycloSal phosph(on)ate prodrug metabolites on BxPC3 pancreatic cancer cells, GL261-Luc glioblastoma cells, and primary cultured mouse astrocytes. 1-Naphthol and 2-naphthol demonstrated the greatest toxicity. Notably, 2-naphthol exhibited an ED of 21 μM on BxPC3 cells, surpassing 1-naphthol with an ED of 82 μM. Real-time xCELLigence experiments revealed notable activity for both metabolites at a low concentration of 16 μM. On primary cultured mouse astrocyte cells, all prodrugs exhibited reduced viability at 128 to 256 μM after only 4 hours of exposure. A cell-type-dependent sensitivity to phosph(on)ate prodrug metabolites was evident, with normal cells showing greater susceptibility than corresponding tumour cells. The results suggest it is essential to consider the potential cytotoxicity of phosph(on)ate prodrugs in the drug design and evaluation process.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11109934 | PMC |
| http://dx.doi.org/10.1039/d4md00115j | DOI Listing |
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