Design and synthesis of novel camptothecin/5-fluorouracil conjugates as cytotoxic agents

In an effort to overcome several limitations associated with the synthesis of camptothecin (CPT), seven conjugates (10a-10g) composed of CPT and a 5-fluorouracil derivative joined by suitable dipeptide linkages were synthesised, and their cytotoxic activity against four human tumour cell lines as well as an in vitro pharmacokinetic determination of their lactone stability were studied. Among these compounds, most tested conjugates showed cytotoxic activities comparable or superior to CPT-11 (2), but they were less potent when compared with CPT (1). Interestingly, all of the compounds showed selective inhibitory activities against BGC-823, with IC₅₀ values lower than 0.1 µmol, which is more potent than CPT-11 (2). Also, the in vitro pharmacokinetic determination of the lactone levels of the representative compound 10b showed that the biological life span of their lactone forms in human and mouse plasma were significantly increased when compared with their mother compound CPT (1).