New antiglioma zwitterionic pronucleotides with an FdUMP framework

Area of Science:

• Medicinal Chemistry
• Oncology
• Pharmacology

Background:

• Glioblastoma multiforme is an aggressive brain tumor with limited treatment options.
• Developing novel therapeutic agents with improved efficacy and delivery is crucial.
• Pro-nucleotides offer a strategy to enhance drug delivery and cellular uptake.

Purpose of the Study:

• To design and synthesize novel 5-fluoro-2'-deoxyuridine 5'-phosphate pronucleotides.
• To evaluate the anti-malignant potency and selectivity of these compounds against various cancer cell lines.
• To investigate the potential mechanism of action and oral bioavailability of promising candidates.

Main Methods:

• Synthesis of sixteen novel zwitterionic pronucleotides.
• In vitro testing of anti-cancer activity against glioblastoma (T98G, U-118 MG, U-87 MG), HeLa, and Caco-2 cell lines.
• Assessment of cytotoxicity using MRC-5 healthy cells to determine selectivity indices.
• Evaluation of intestinal-blood uptake using the Caco-2 cell line.

Main Results:

• Five compounds (4c, 4f-i) displayed significant anti-cancer potency.
• Selectivity indices ranged from 12 to 66, indicating high selectivity for cancer cells.
• Compounds 4c and 4f-h showed high intestinal-blood uptake potential.
• A proposed mechanism involves inducing cell membrane charge disorder.

Conclusions:

• The synthesized zwitterionic pronucleotides exhibit promising anti-cancer activity against glioblastoma.
• Compounds 4c, 4f-h are identified as potential orally administered anticancer drugs due to their uptake characteristics.
• Further investigation into their therapeutic potential is warranted.