Nucleoside analogues, such as the fluorinated pyrimidines are widely used for the treatment of cancer. The highly charged nature of the 5'-phosphates means they are not able to penetrate the cell membrane, which can limit their direct therapeutic potential. We have developed ProTide technology, that allows 5'-monophosphates to cross biological membranes, bypassing active transport. The family of compounds were tested for their anti-proliferative effects in different cancer cell lines, with or without thymidine kinase.FUDR ProTides were synthesised using phosphorochloridate chemistry.The majority of the compounds retained the high potency of FUDR. They showed nanomolar IC50 values against different tumor cell lines and partially bypass the high dependence of the parent nucleoside on kinase-mediated activation and on cell transporter-mediated uptake.The ability of the ProTides to overcome several sources of resistance associated with FUDR in the clinic suggests that these agents should be further progressed towards clinical trials.

Synthesis and biological evaluation of FUDR monophosphate prodrugs as anticancer agents

244th National Meeting (2012)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.