Syntheses And Antitumor Activities Of Amino Acid Derivatives Containing 5-Fluorouracil

5-Fluorouracil(5-FU) is an antimetabolite of the pyrimidine analogue type,with a broad spectrum of activity against solid tumors,including colorectal,gastric,liver carcinomas etc. However,the clinical applications of 5-FU are subjected to great limitations because of its short plasma half-life,poorly tumor selectivity,bone marrow suppression,intestinal toxicity and so on.Therefore,people have been attempting to develop new prodrugs of 5-FU as lead compounds with high efficiency and low toxicity.Amino acids and peptides have good affinity with cells and nucleic acids,in which drug molecules would quickly arrive at when they are introduced to the peptide chain backbone. We designed and synthesized different kinds of amino acid compounds containing fluorouracil in order to reduce its side effects and search for new potential prodrugs with low toxicity and high efficiency by in vitro activity tests.5-Fluorouracil reacted with bromoacetic acid in sodium hydroxide solution at controlled temperature to prepare the intermediate 5-fluorouracil-1-yl acetic acid(5-FUAA).A series of 5-fluorouracil-1-yl-aceto amino acid esters were synthesized when 5-FUAA condensated with different kinds of amino acid esters by 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(EDCI) and N-Hydroxybenzotriazole(HOBt) as a coupling reagent,the corresponding 5-fluorouracil-1-yl-aceto amino acids were obtained after hydrolysis by controlling the temperature and pH;As a starting material,5-fluorouracil-1-yl-acetamido acetic acid condensated with four different amino acid esters by EDCI to prepare four kinds of 5-fluorouracil-1-yl-aceto-glycyl amino acid esters,and the corresponding 5-fluorouracil-1-yl-aceto-glycyl amino acids were obtained after hydrolysis.The structures of the above compounds were assigned by nuclear magnetic resonance,mass spectrometry,and infrared spectroscopy etc.The in vitro antitumor activity tests for 5-fluorouracil-1-yl-aceto amino acid esters were carried out by comparison of 5-FU and FT-207.The result indicated that all the compounds had better tumor suppression than FT-207,and the inhibition rates of R-type compounds are higher than those of S-type compounds at high concentration(10^-4 mol/L);The rapid decrease of inhibitory effects when the concentration declined implied the complexity of the antitumor mechanism.(R)-methyl 2-(2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) acetamido)-3-phenylpropanoate(3-3i-2) and(R)-ethyl 2-(2-(5-fluoro-2,4-dioxo-3,4-dihydropy rimidin-1(2H)-yl)acetamido)-3-(4-hydroxyphenyl) propanoate(3-3k) showed good inhibition rate against BEL-7402,SW-480 and Hela,which related to their R configuration,and the relative rigid structure composed of pyrimidine and phenyl ring.The in vitro biological activity tests of the four 5-fluorouracil-1-yl-acetamido-glycyl amino acid esters indicated that they had poor tumor suppression even at high concentration(10^-4 mol/L) due to the increased water solublity and the poor lipid sloublity causing the decrease of oil/water partition coefficient.