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目的通过合成系列熊果酸衍生物,测试其抑制肿瘤细胞增殖活性,探讨熊果酸衍生物抑制肿瘤细胞增殖的构效关系,获得抗肿瘤活性更好的熊果酸衍生物。方法通过乙酰化反应对熊果酸的3-位羟基进行保护后,再将其28-位羧基制备成酰氯并与氨基酸酯反应,最后再在碱性条件下水解制备得28-位羧基被修饰的熊果酸衍生物。所有熊果酸衍生物的结构通过核磁共振氢谱(~1HNMR)、核磁共振碳谱(~(13)CNMR)和高分辨质谱(HRMS)进行确认。采用MTT法测试熊果酸衍生物抑制U937、HL-60、Jurkat、K562、DU145、EC109、MDA231和SMMC7721肿瘤细胞的增殖活性。结果仪器分析结果表明所制备的熊果酸衍生物均为设计的目标化合物。对抑制U937肿瘤细胞增殖结果表明熊果酸28-位羧基被对4-氨甲基苯甲酸、7-氨基己酸和8-氨基辛酸修饰后,在给药浓度为5.0×10~(-6)mol/L时对U937细胞增殖的抑制率分别达到(18.84±2.58)%、(43.17±4.52)%和(68.38±7.95)%,明显优于母体熊果酸母体(10.06±2.35)%(P<0.05)。对Jurkat细胞增殖的抑制率则分别达到(68.42±8.19)%、(58.36±7.99)%和(61.08±5.77)%,远高于熊果酸的(6.89±2.31)%(P<0.05)。结论对熊果酸28-位羧基进行延长修饰,有利于提高熊果酸的抗肿瘤活性,当延长7~8个碳原子,抗肿瘤效果最好。
OBJECTIVE: To synthesize a series of ursolic acid derivatives and test their inhibitory effect on the proliferation of tumor cells. To study the structure-activity relationship of ursolic acid derivatives inhibiting the proliferation of tumor cells and to obtain ursolic acid derivatives with better anti-tumor activity. Methods After protecting the 3-position hydroxyl of ursolic acid through acetylation, the 28-position carboxyl group was prepared as acid chloride and reacted with amino acid ester. Finally, the 28-position carboxyl group was modified by hydrolysis under basic conditions Ursolic acid derivatives. The structures of all ursolic acid derivatives were confirmed by 1H nuclear magnetic resonance (~ 1HNMR), nuclear magnetic resonance (~ (13) CNMR) and high resolution mass spectrometry (HRMS). The UA activity of U937, HL-60, Jurkat, K562, DU145, EC109, MDA231 and SMMC7721 tumor cells was tested by MTT assay. Results The instrumental analysis showed that the prepared ursolic acid derivatives were all designed target compounds. Inhibition of U937 tumor cell proliferation results show that the ursolic acid 28-carboxyl is modified by 4-aminomethyl benzoic acid, 7-aminocaproic acid and 8-aminooctanoic acid at a concentration of 5.0 × 10 -6 ) inhibited the proliferation of U937 cells by (18.84 ± 2.58)%, (43.17 ± 4.52)% and (68.38 ± 7.95)%, respectively, which was significantly better than that of maternal ursolic acid (10.06 ± 2.35)% P <0.05). The inhibitory rates of Jurkat cell proliferation were (68.42 ± 8.19)%, (58.36 ± 7.99)% and (61.08 ± 5.77)%, respectively, much higher than that of ursolic acid (6.89 ± 2.31)% (P <0.05). Conclusion Prolonged modification of the 28-carboxyl group of ursolic acid helps to increase the anti-tumor activity of ursolic acid. When prolonged by 7-8 carbon atoms, the anti-tumor effect is the best.