Amino acid ester prodrugs of the anticancer agent cytarabine: Prodrug synthesis, stability, bioconversion and permeability

Cytarabine, also known as Ara-C, is a clinically effective antimetabolite anticancer agent. Ara-C is widely used in myelogenous leukemia, non-Hodgkin lymphoma etc. It is a drug with low membrane permeability and is administered intravenously. Thus strategies that increase permeability and mainly bioavailability through oral route may be clinically effective. In order to achieve this, the amino acid ester prodrugs of Ara-C were synthesized by using aliphatic amino acids Boc-L-Val-OH and Boc-L-Ile-OH. The objective of this study was to evaluate whether the amino acid ester prodrugs of Ara-C would facilitate transport across the intestinal membrane. The prodrugs were synthesized by peptide synthesis and the pure product was obtained by liquid column chromatography. The product was then examined as a substrate of carboxypeptidase and also for chemical stability in PBS. The cytotoxicity against Hela and Caco-2 cell lines were also examined by XTT assay. Amino acid ester prodrugs of Ara-C were also checked for permeability through the Caco-2 monolayer intestinal epithelial membrane. The results show that amino acid ester prodrugs of Ara-C (Val-Ara-C and Ile-Ara-C) were able to convert to the parent drug Ara-C in Caco-2 cell homogenates. Their chemical stability in PBS was comparable to some of the commercially marketed oral amino acid ester prodrugs like valcyclovir and valganciclovir. The rate of bioconversion following transport across the intestinal epithelial membrane controls the disposition of Ara-C following oral administration as exhibited by the enzymatic bioconversion of prodrugs in Caco-2 cell homogenate. The results suggest that it might be possible to modulate these characteristics by the appropriate choice of the amino acid promoiety.