穿心莲二萜内酯类化合物的合成及抗肿瘤构效关系研究

 目的合成穿心莲二萜内酯类化合物,并进行抗肿瘤活性研究。方法以穿心莲内酯为底物合成14-去氧-11,12-二去氢穿心莲内酯、14-去氧穿心莲内酯、异穿心莲内酯和穿心莲酸等穿心莲二萜内酯类化合物。以人白血病HL-60为体外模型,小鼠H22肝癌皮下移植肿瘤为体内模型观察其抗肿瘤活性,同时观察对小鼠迟发性变态反应及碳粒廓清功能的影响。结果目标物结构经红外、质谱、核磁共振氢谱确证。体外实验,异穿心莲内酯和穿心莲内酯对HL-60细胞的IC₅₀分别为7.15和28.34μmol·L^-1,其余化合物均大于50μmol·L^-1;体内实验,筛选剂量为100mg·kg^-1时,穿心莲内酯和异穿心莲内酯有明显的抗肿瘤活性,抑制率分别为64.4%和61.2%,其余化合物抗肿瘤活性不明显;相同剂量下,穿心莲内酯,穿心莲酸对迟发性变态反应有促进作用,穿心莲内酯,穿心莲酸,14-去氧穿心莲内酯,14-去氧-11,12-二去氢穿心莲内酯能降低小鼠碳粒廓清指数,而异穿心莲内酯对迟发性变态反应和炭粒廓清指数均无影响。结论初步生物活性实验表明,穿心莲二萜内酯类化合物的内酯环是抗肿瘤的必须活性基团;该类化合物的抗肿瘤作用可能与内酯环部分(包括C₁₁和C₁₂)双键的个数及位置和14-位羟基均有一定关系,具有环外12,13-位双键和14-位羟基的抗肿瘤活性较强;异穿心莲内酯的四氢呋喃环有增强抗肿瘤活性之作用。异穿心莲内酯有非常显著的抗肿瘤活性,且对小鼠免疫功能无影响,提示它可能是一类有发展前景的抗肿瘤药物。

Studies on Synthesis and Antitumor Structure-Activity Relationship of Diterpene Lactones of Andrographis panniculata Nees

OBJECTIVE To synthesize diterpene lactones of Andrographis panniculata Nees and study antitumor structure-activity relationship.METHODS 14-deoxy-11,12-didehydroandrographolide,14-deoxyandrographolide,isoandrographolide and andrographolide acid were synthesized from andrographolide.The antitumor activities were observed in leukemia HL-60 cells and in hepatoma H22-implanted mice,the immune functions were tested by delayed type hypersensitivity(DTH) and charcoal particle clearence in mice.RESULTS The structures of the synthesized compounds were confirmed by IR,MS and 1 H-NMR.In vitro,IC₅₀ of compound isoandrographolide and andrographolide was 7.15 and 28.34 μmol·L^-1 respectively in HL-60 cells,others were more than 50 μmol·L^-1.In vivo,compound andrographolide and isoandrographolide had significent antitumor activities at the dose of 100 mg·kg^-1 with 64.4% and 61.2% suppression respectively in subcutaneous H22-implanted mice,others had no effect on tumor growth.At the same dose,the DTH was promoted by compound andrographolide and andrographolide acid and the charcoal particle clearance coefficient was decreased by compound andrographolide,andrographolide acid,14-deoxyandrographolide and 14-deoxy-11,12-didehydroandrographolide,but both were not affected by compound isoandrographolide.CONCLUSION The preliminary pharmacological studies indicated that the lactam ring of the andrographolides is necessary for antitumor activities and the number and site of the double bonds of the five-number lactam ring and 14-OH might be related to antitumor activities.The antitumor activities that with 12,13-double bonds and 14-OH are much stronger.THF ring of isoandrographolide can boost up the antitumor activities possibly.isoandrographolide has better antitumor activities and has no effect on the mice immune function,which suggested that isoandrographolide might be a useful antitumor drug.