摘要
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。
Abstract
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.
关键词
穿心莲二萜内酯类化合物
{{custom_keyword}} /
Key words
diterpene lactones of Andrographis panniculata Nees /
antitumor activities /
immune functions
{{custom_keyword}} /
韩光;杜钢军;许启泰.
穿心莲二萜内酯类化合物的合成及抗肿瘤构效关系研究[J]. 中国药学杂志, 2008, 43(10): 790-794
HN Gung;DU Gng-jun;XU Qi-ti.
Studies on Synthesis and Antitumor Structure-Activity Relationship of Diterpene Lactones of Andrographis panniculata Nees [J]. Chinese Pharmaceutical Journal, 2008, 43(10): 790-794
{{custom_sec.title}}
{{custom_sec.title}}
{{custom_sec.content}}
参考文献
[1] Jiangsu College of New Medicine Science.Thesaurus of Chinese Traditional Medicine (中药大辞典)[M] . Shanghai：Shanghai Science & Technology Press，1986：1728.
[2] MADAR S，TRIPATHI H C. Antipyretic and anti-alcerogenic effects of andrographolide[J] . Indian J Pharm Sci，1995，57(3)：121-125.
[3] SIRIPONG P，KONGKATHIP B，PREECHANUKOOL K. Cytotoxic diterpenoid constituents from Andrographis panicucata Nees，leaves. Ect[J] . J Sci Soc Thailand，1992，18(4)：187-194.
[4] CHOUDHURY B R，PODDAV M K. Andrographolide and kalmegh (Andrographis paniculata) extract： effect on rat liver and serum transaminases[J] . IRCS Med Sci，1984，12(6)：466-467.
[5] VISEN P K S，SHUKLA B，PATNAIK G K，et al. Andrographolide protects rat hepatocytes against paracetamol induced damage[J] . J Ethnopharmacol，1993，40(2)：131-136.
[6] KOUL I B，KAPIL A. Effect of diterpenes from Audrographis paniculata on anti-oxidant defense system and lipid peroxidation[J] . Indian J Pharmacol，1994，26(4)：296-300.
[7] SANASWAT B，VISEN P K S. Effect of andrographolide agaist glalactosamine-induced hepatotoxicity[J] . Fitoterapia，1995，66(5)：415-420.
[8] TRIPATHI G S，TRIPATHI P. Choleretic action of androgr apholide obtained from Andrographis panicalata in rats[J] . Respirology，1991，5(4)：176-178.
[9] PUKI A，SAXENA R P. Immunostimulant agents from Andrographis paniculata[J] . J Nat Prod，1993，56(7)：995-999.
[10] PENG G Y ，ZHOU F. Modulation of Lianbizi Injection ( Andrographolide)on some immune functions[J] . China J Chin Mater Med（中国中药杂志），2003，27（2）：147-150.
[11] BASAK A，COOPER S. Inhibition of proprotein convertases-1，7-and furin by diterpines of Andrographis paniculata and their succinoyl esters[J] . Biochem J，1999，338(Pt1)：107-113.
[12] CHANG R S，DING L. Dehydroandrographolide succinic acid monoester as an inhibition agaist the human immunodeficiency virus[J] . Proc Soc Exp Biol Med，1991，197(1)：59-66.
[13] CHION W F. Andrographolide suppress the expression of inducible nitric oxide synthase in macrophage and restores the vasoconstriction in rat aorta treated with hipopolysacharide[J] . Br J Pharmacol，1998，125(2)：327-334.
[14] WU J L，LIU S Z. Protective effect of andrographolide on experimental myocardial infarction rats[J] . Res Tradit Chin Med(中医药研究)，1996，（4）：61-64.
[15] LIU X G，PAN S P. The study of anti-pregnancy effect of dehydroandrographolide derivatives[J] . J Jinan Univ (Natural Sci Med Edit)(暨南大学学报，自然科学与医学版）），1987（1）：91-96.
[16] ALAN B，JOSEPHD C. Minor diterpenoid constituents of andrographis paniculata nees[J] . J Chem Soc Perkin，1973，24（6）：1247-1251.
[17] CAVA M P. Andrographolide further transformation and stereochemical evidence：the struture of isoan-drographolide[J] . Tetrahedron，1965，21（3）：2617-2623.
[18] CHAKRAVARTI D，CHAKRAVATI R N. Andrographolide. Part Ⅰ[J] . J Chem Soc，1952，16（8）：1697-1704.
[19] XU S Y. Methodology of Medicine′s Pharmacological Research (2nd ed) (中药药理研究方法学)（第2版） [M] . Beijing：People′s Health Press，1992：1223-1224.
[20] XU S Y.Methodology of Medicine′s Pharmacological Research (2nd ed)(中药药理研究方法学)（第2版）[M] . Beijing：People′s Health Press，1992：1429-1430.
[21] SUN Y，WANG J M . The effect of epimedium pubescen maxin(EPM)on MPS phagocytosis and erythrocyte immunee adherence in immunodepressant mice and correlation study[J] . Chin J Immunol(中国免疫学杂志)，2002，18（2）：114-119.
[22] MAHESH P, MEENAKSHI S, SHARMA R P. Chemical transformation of andrographolide[J] .Indian J Chem，2002，41B，1915-1918.
[23] NANDURI S. Anticancer compounds：process for their preparation and Pharmaceutical compositions containing them：US，6486196[P] . 2002-11-26.
[24] NANDURI S. Compounds having antitumor activity：process for their preparation and Pharmaceutical compositions containing them：US，6410590[P] . 2002-06-25.
[25] NANDURI S. Compounds having antitumor activity：process for their preparation and Pharmaceutical compositions containing them. USP6576662. [P] .2003-06-10.
[26] NANDURI S. Synthesis and structure-activity relationship of andrographolide analogues as novel cytotoxic agents[J] . Bioorg Chem Lett，2004，14(18)： 4711-4719.
{{custom_fnGroup.title_cn}}
脚注
{{custom_fn.content}}
基金
河南省重点科技攻关项目[0623030200]
{{custom_fund}}
