New antiglioma zwitterionic pronucleotides with an FdUMP framework

  • Eur J Med Chem. 2018 Jan 20:144:682-691. doi: 10.1016/j.ejmech.2017.12.070.
Agnieszka Szymanska-Michalak  1 ,  Dariusz Wawrzyniak  1 ,  Grzegorz Framski  1 ,  Jacek Stawinski  1 ,  Jan Barciszewski  1 ,  Adam Kraszewski  2
Affiliations
  • 1. Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704, Poznan, Poland.
  • 2. Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704, Poznan, Poland. Electronic address: [email protected].
PMID: 29289891 DOI: 10.1016/j.ejmech.2017.12.070
Abstract

We have designed and synthesized new 5-fluoro-2'-deoxyuridine 5'-phosphate pronucleotides which can function as potential agents against the glioblastoma multiforme tumor. Their anti-malignant potency has been tested against T98G, U-118 MG, U-87 MG gliomas, HeLa, and Caco-2 Cancer cell lines, using MRC-5 healthy cells as a reference. Five of the sixteen compounds (4c, 4f-i) exhibited significant Anticancer potency and high selectivity indices (SI 12-66). It is likely that these zwitterionic pronucleotides may function in a similar manner to zwitterionic Phospholipids, by inducing cell membrane charge disorder, making the cell permeable to bioactive agents. The most promising therapeutic pronucleotides 4c, 4f-h, have high intestinal-blood uptake potency (Caco-2 cell line), and may be considered as potential, orally administrated, Anticancer drugs.

Keywords
Anticancer; FdUMP; GBM; Glioblastoma multiforme; Nucleotide analogues; Pronucleotides; Zwitterions.