Design, Synthesis And Activity Evaluation Of 5-Fluorouracil Derivatives As Antitumor Agent

5-fluorouracil (5-FU) as antimetabolite antineoplastic agents is dramatically toxicitive due to the poor selectivity although it is of broad-spectrum, high effect, and wide usage because of thymidylate synthase inhibition and DNA synthesis disturbance. In the light of the higher activity of amide hydrolase and reductase, and the lower pH value in tumor cell than in normal cell, conjugation of aryl carboxylic acid,2-(2-nitrophenyl)acetic acid or its analogues with the position 1 or 3 of 5-FU gave 13 5-FU derivatives which were identificated by IR,1H-NMR,13C-NMR, MS and HRMS.The synthesis optimization gave the more than 50% yield of N1 derivatives. The LogP measured by UV of 10 compounds was higher than the one of 5-FU (-0.55).The inhibition determination of 4 derivatives in 3 tumor cell lines (K562, MGC-830, A549) by MTT method gave the half inhibitory concentration (IC50). The IC50 was significantly lower than the one of 5-FU in MGC-830, the inhibition rates were so, too. The inhibition rate was also higher in K562 than the one of 5-FU although the IC50 was obviously higher in K562 and A549 than the ones of 5-FU.The experimental model of S180 tumor-bearing mice and LD50 determination by improved Karber method systematically evaluated the antitumor activities of target compounds. LD50 of the new compounds was at least less 0.5 times than the one of 5-FU. However, the inhibitory rates in the low dose of the 9 compounds except for compound 2,7,9, and 11 were more than the ones in the mediate dose, even in the high dose of 5-FU. It suggested that their normal doses of the 9 compounds be at least lower 0.3 to 0.6 time than the one of 5-FU. Meanwhile, the 9 compounds damaged the immunogical organs siganificantly less than 5-FU. The discovery provided the foundation for more potent and selective antitumor agents and further investigation.