Development of Isoleucine Prodrugs of Cytarabine

Cytarabine is an intravenous chemotherapeutic agent that is commonly used for treatment of white blood cell cancers such as acute myeloid leukemia, non-Hodgkin lymphoma, and lymphoblastic leukemia. Cytarabine is a polar nucleoside that has a short plasma half-life and less than ideal permeability which limits its efficiency. Cytarabine also has a long list of side effects which limit its clinical utility. In this study an amino acid ester prodrug of cytarabine was synthesized with the expectation to improve penneability and enhance cytotoxicity in HL-60, MOLT -4, and K562 leukemia cell lines. Multistep protection and deprotection reactions of Boc protected isoleucine and cytarabine resulted in the synthesis of an amino acid ester prodrug of cytarabine. The purity of the prodrug was determined by HPLC and confirmed by proton nuclear magnetic resonance. The results showed that the isoleucine-cytarabine prodrug was cytotoxic to K562 cells with 67.3% inhibition (24hr with 100uM), 42.3% inhibition in MOLT-4 cells (24hr with 100f.LM), and 59.6% inhibition in HL-60 cells (24hr with 1 OOuM). The inhibition percentage in K562 cells with1 Of.LM prodrug treatment concentration was 19% higher compared to the cytarabine equivalent at 24hr. The antitumor effects of this amino acid ester prodrug of cytarabine make it a good candidate for fmiher study