Synthesis and anticancer activities of amphiphilic 5-fluoro-2′-deoxyuridylic acid prodrugs

Abstract

Amphiphilic anticancer prodrugs of 5′-fluoro-2′-deoxyuridine-5′-monophosphate (5-FdUMP) were synthesized according to the hydrogen phosphonate method by coupling lipophilic cytosine derivatives or a phospholipid with 5-fluoro-2′-deoxyuridine (5-FdU). Studies within the in vitro Anticancer Screen Program of the National Cancer Institute have demonstrated high anticancer activities of the heterodinucleoside phosphates: N 4-palmitoyl-2′-deoxycytidylyl-(3′ → 5′)-3′- O-acetyl-5-fluoro-2′-deoxyuridine (dC pam-5-FdU(Ac), N 4-palmitoyl-2′,3′-dideoxycytidylyl-(5′ → 5′)-3′- O-acetyl-5-fluoro-2′-deoxyuridine (ddC pam-(5′ → 5′)-5-FdU(Ac), 5-fluoro-2′-deoxyuridylyl-(3′ → 5′)-5-fluoro-N 4-hexadecyl-2′-deoxycytidine (5-FdU-5-FdC hex), and of the new liponucleotide 1- O-octadecyl-rac-glycerylyl-(3 → 5′)-5-fluoro-2′-deoxyuridine (Oct 1Gro-(3 → 5′)-5-FdU). The anticancer activities of these prodrugs are comparable to those of 5-FdU and the tumor specificities are modulated by their structures. The highest cytotoxic activity being even superior to 5-FdU was expressed by the dimer 5-FdU-5-FdC hex.