3-羧烷酰氧基-(11-氧代)-乌苏烷-12-烯-24-羧酸酯类化合物的合成及抑制白血病细胞生长和诱导凋亡活性的研究

The synthesis and apoptotic effect of 3-carboxyalkylcarbonyloxy-(11-oxo-)urs-12-ene-24-oate derivatives in human leukemia HL-60 cells

目的对乳香酸进行结构改造,增强其抑制白血病细胞生长和凋亡诱导活性。方法以乳香的提取物乳香酸乙酸酯为起始原料,经过水解、酯化得到目标化合物。以台盼蓝排斥试验和AO-EB双荧光染色法检测乳香酸类化合物对人白血病细胞HL-60的生长抑制作用及凋亡诱导作用。结果与结论合成了15个乳香酸类化合物,其中11个化合物III、IIaI、IIbI、Va^IVd、Va^Vc、VIII为未见文献报道的新化合物。目标化合物的结构经核磁共振氢谱、质谱进行确证。对其中5个化合物抑制白血病细胞生长和诱导凋亡活性进行了研究,初步的药理实验结果表明,3-丙酰氧基-齐墩果烷型(乌苏烷型)-12-烯-24-羧酸(VIIa)具有较强的细胞生长抑制作用和凋亡诱导作用。

Aim To modify boswellic acid structure for increasing its antileukemia activity. Methods Boswellic acid acetate and 11-oxo-boswellic acid acetate were hydrolyzed and then esterified or etherified to obtain target compounds with different substitutes. Cell growth inhibitory effect was measured by directly counting of cell numbers after treatment with these compounds. Apoptotic cells were evaluated morphologically after staining with acridine orange and ethidium bromide in HL-60 cells. Results and conclusion Fifteen deriva- tives of boswellic acid including 11 novel compounds （Ⅱ、Ⅲa、Ⅲb、Ⅳa-Ⅳd、Ⅴa-Ⅴc、Ⅷ） were synthesized and their structures were characterized according to the spectra of ^1H-NMR and MS. Compound VIIa with a replacement of acetyl group in boswellic acid acetate by a propionyl group, has stronger cell growth inhibitory and apoptotic effect than compounds with removed acetyl group or esterified carboxylic acid.