Study On Ursolic Acid And Its Derivatives Bond With 5-fluorouracil Derivatives And Antitumor Activities

AimMalignant tumors, has become a prone and common diseases, which threaten the lives and health of human beings seriously, and affect the quality of people’s life greatly. Those are still public health problems globally. The total number of new cancer cases has been increasing constantly.5-fluorouracil(5-FU), chemical name is 5-fluoro-2,4(1H,3H)-pyrimidinedione, as a thymidylate synthase inhibitor. 5-FU has a good,widely antitumor activity but highly toxicity, which is a preferred drug for solid tumors.Ursolic acid(UA) are pentacyclic triterpenoids, having varieties of biological activity,such as anti-cancer, anti-inflammatory, anti-diabetic, anti-virus, protecting liver, enhancing immune system and preventing cardiovascular diseases. Anticancer activity is the most valuable pharmacological activity among all the biological activities, and it also showed a fewer side effects, lower toxicity, which showing a great potential for clinical application.The main purpose of this project was using ursolic acid and 5-fluorouracil as lead compounds, guided by organic chemistry theory, to design and synthesize the derivatives of5-fluorouracil and ursolic acid. Then tested with biological activity to find a novel compound which has highly anti-cancer activity as 5-fluorouracil and also has varieties of pharmacologically active as ursolic acid.Methods1.With 5-fluorouracil-based structure, the introduction of acetate group to get intermediate 5-fluorouracil-1-yl acetic acid in its three nitrogen. Intermediate5-fluorouracil-1-yl acetic in the solvent of N,N-dimethyl-Formamide(DMF),With4-dimethylaminopyridine(DMAP) as a alkali, Dicyclohexylcarbodiimide(DCC) as a dehydrating agent, esterify with 3-hydroxy of Ursolic acid and its derivatives to synthesize the target product.2. The growth inhibiting rates of the target compound and ursolic acid on Hela cells and human hepatoma cells(Bel-7402) were evaluated by using MTT assay.ResultsThese novel compounds were synthesized successfully and the structures of which were determined by1 HNMR, IR,13 CNMR and MS as 3-O-(2’-(5’-fluorouracil-1’-) acetyl)– ursolic, 3-O-(2’-(5’-fluorouracil-1’-) acetyl) – ursolic methyl ester, 3-O-(2’-(5’-fluorouracil-1’-) acetyl) – ursolic ethyl ester, 3-O-(2’-(5’- fluorouracil-1’-) acetyl) –ursolic propyl ester, 3-O-(2’-(5’- fluorouracil-1’-) acetyl) – ursolic butyl ester. And in vitro the growth inhibiting rates of 3-O-(2’-(5’- fluorouracil-1’-) acetyl) – ursolic on Hela cells and Bel-7402 cells for 6.6 ummol/L,6.8 ummol/L. 3-O-(2’-(5’- fluorouracil-1’-)acetyl) – ursolic methyl ester on Hela cells and Bel-7402 cells for 26.62 ummol/l,6.77ummol/L. 3-O-(2’-(5’-fluorouracil-1’-) acetyl) – ursolic ethyl ester on Hela cells and Bel-7402 cells for 27.13 ummol/l and 8.35 ummol/l.3-O-(2’-(5’- fluorouracil-1’-) acetyl) –ursolic propyl ester on Hela cells and Bel-7402 cells for 22.15 ummol/l and 13.05ummol/l.3-O-(2’-(5’-fluorouracil-1’-) acetyl) – ursolic butyl ester on Hela cells and Bel-7402 cells for 35.68 ummol/l and 9.13 ummol/l. Compare to the anti-tumor activity of ursolic acid and 5- fluorouracil were significantly improved.(UA,63.76μmol/L,34.7μmol/L;5-fluorouracil, 961μmol/L, 35.84μmol/L).ConclusionsThe anti-tumor activity of ursolic acid and 5-fluorouracil were significantly improved, as 5-fluorouracil bonded to the ursolic acid. The results provide a certain reference for searching more effective anti-cancer compounds and a way for structural modify for Natural active pharmaceutical ingredients.