Synthesis Of Novel 5-Fluorouracil Derivatives And Evaluation Of Their Preliminary Anti-tumor Activity

As a kind of pyrimidine first-line antitumor drug in clinic,5-fluorouracil (5-Fu) has widely inhibition effects on many kinds of neoplasms with broad-spectrum antitumor activity. It exerts antitumor activity by converting 5-Fu into 5-fluorouracil deoxyuridine monophosphate (5F-dUMP) in cells to inhibit the activity of thymidylate synthase. However, it also has a varity of drawbacks, such as its low lipid solubility, significant first pass metabolism effect, serious side effects owing to the similar doses between treatment and toxicity, and unstable oral bioavalability due to the short half-life time, resulting its its limited application in clinic. Therefore, many efforts are made on chemical modification of 5-Fu to overcome these shortcomings. Many 5-Fu derivatives via appropriate derivatization (e.g., Tegafur, Carmofur, Capecitabine, Floxuridine) have offered improved antitumor activity and reduced cytotoxicity with convenient route of administration, in comparison with the prototype drug 5-Fu, suggesting the structural modifications on 5-Fu is feasible and an important approach to improve its efficacy.Fatty acid (FA) synthase is a key multi-enzyme protein that catalyzes FA synthesis and participates in the formation of lipophilic substances that are essential for the formation of cell membrane. Evidence has revealed that it is selectively expressed in many kinds of tumor cells, but almost has no expression in normal cells. This is based on the fact that normal cells usually need a certain amounts of lipophilic Fas to satisfy the energy production, storage, and cellular structure formation. In the case of tumor cells, they normally need to absorb a large amount of exogenous Fas in order to meet the demands of rapid proliferation. Based on this, in our project, we introduced various long chain FA side chains to 5-Fu, aiming to simulate exogenous Fas and reach tumor cells as a novel type of tumor-targeting drug delivery system. Once reaching to the lesion site, the linkage bonds will be easily broken under the action of various hydrolytic enzymes and the 5-Fu will be released to exert it tumor-targeting antitumor effect. Additionally, this FA-modified drug delivery system can adjust the ester water distribution coefficient (LogP), leading to the enhanced bioavailability of 5-Fu. Moreover, the introduction of the FA substitutions can increase the liposolubility of compounds, resulting in the prolonged efficacy of target drug.In the present work, we obtained total 18 compounds on the 1-NH position of 5-Fu via esterification and acylation. Among the resulting FA-modified 5-Fu prodrugs,8 were evaluated the antiproliferative activities on HCT116 tumor cell lines by MTT assay. The results showed that compounds 4b,4c,4d,4e are expected to develop into potential antitumor drugs. Further studies of these FA-modified 5-Fu prodrugs are on-going in our lab.