Glycine-proline monoester prodrug of the anticancer agent cytarabine

Cytarabine, a pyrimidine nucleoside analogue is a highly effective antimetabolite used in the treatment of acute lymphocytic leukemia, non-Hodgink's lymphoma and lymphomas. It is a polar drug with low membrane permeability and poor oral bioavailability, hence administered intravenously or intrathecally, that leads to high treatment cost and incompliance in patients. Thus strategies that increase permeability and most importantly bioavailability through oral route may be helpful to defeat this drawback. To overcome these drawbacks and for development of an oral alternative, the amino acids prodrug of Cyatarbine were synthesized using dipeptide BocGlycine-Proline-OH. The main objective of the study was to evaluate whether the dipeptide amino acid prodrug would facilitate transport across the intestinal membrane.;The di-peptide prodrug was synthesized by Staglich esterification synthesis process which yields 3'- dipeptide ester, 5'-dipeptide ester and 3', 5'-tetrapeptide ester prodrug of Cytarabine, but the previous study on Gemcitabine and FuDR (Flouxouridine) amino acid prodrug showed the 5'-ester prodrug was only effective hence in this study only the 5'-ester prodrug was examined. The combination mixture of prodrugs was separated and purified by column chromatography. The chemical stability of the prodrug was examined in PBS (pH 7.4), at pH 2(high acidic) and pH 5. Amino acid ester prodrugs of Cytarabine were also characterized for permeability study using the Caco-2 monolayer intestinal epithelial membrane. The cytotoxic effect of the prodrug was then checked against Caco-2 cells and HeLa Cells. The result showed that membrane permeability of the prodrug was more compared to the parent drug Ara-C. The prodrug (Gly-Pro-AraC) was also found to be chemically stable at all pHs in this study and having a good half-life of more than ∼8 hours which could comparable to other commercially available prodrug like Valacyclovir and Valganciclovir.;These results suggests that it might be possible to modulate prodrug characteristics by the appropriate choice of the amino acid promoiety and the further study with the oligopeptide transporters (hPEPT1) might help in proper selection of amino acids.