β-榄香烯氨基酸衍生物的合成及抗肿瘤活性  

Synthesis and antitumor activity of β-elemene derivatives bearing amino acid moiety

作　　者：徐莉英[1] 张兴忠[1] 杜惠莲[2] 陶淑娟[1] 王宪明[3] 陈光[3] 董金华[1] 

机构地区：[1]沈阳药科大学基于靶点的药物设计与研究教育部重点实验室,辽宁沈阳110016 [2]沈阳医学院附属卫校,辽宁沈阳110034 [3]沈阳药科大学药学院,辽宁沈阳110016

出　　处：《中国药物化学杂志》2013年第3期169-176,共8页Chinese Journal of Medicinal Chemistry

基　　金：国家"重大新药创制"科技重大专项(2009ZX09103-057);辽宁省教育厅创新团队项目(2007T176)

摘　　要：目的设计合成β-榄香烯氨基酸衍生物,并进行体外、体内抗肿瘤活性研究。方法采用烯丙位的氯代反应合成β-榄香烯氯代物,再与氨基酸甲酯反应合成目标化合物。采用磺酰罗丹明B(SRB)染色法测定目标化合物体外对肿瘤细胞增殖的抑制作用,以小鼠腋下移植瘤为模型进行体内抗肿瘤试验,考察化合物5h对Lew is肺癌LL/2、肝癌H22模型的抑制作用。结果共合成15个β-榄香烯氨基酸和β-榄香烯氨基酸甲酯衍生物,其中12个化合物未见文献报道,合成化合物的结构经红外光谱、核磁共振氢谱和质谱确证。大部分目标化合物对人癌细胞HL-60、HeLa、SGC-7901的IC50值低于β-榄香烯。体内试验结果显示,化合物5h对Lewis肺癌LL/2、肝癌H22的生长有显著抑制作用。结论在β-榄香烯结构中引入氨基酸或氨基酸甲酯结构片段有利于提高此类化合物的抗肿瘤活性。β-Elemene is the main component of Elemene emulsion developed in China as an antitumor drug. It possesses high specificity and lower liver and renal toxicities, as well as functions of immunity enhance- ment. To improve its poor water-solubility and antitumor activities, fifteen β-elemene derivatives bearing amino acid moiety were synthesized fromβ-elemene via chlorination and nucleophilic substitution.β-E1- emene （1） was firstly treated with sodium hypochlorite（NaCIO） to generate the mixture of 14-chloro-β-el- emene 2 and 13-chloro-β-elemene （3）. Without further purification, the products were then condensed with a series of methyl esters of amino acids. The products were separated with column chromatography. The struc- tures of all target compounds were confh-med by IR, 1H-NMR and MS. The fifteen β-elemene derivatives have not been reported except compounds 6a,6b ,6e. The effects of synthesized derivatives on growth inhibi- tion against HL-60 ,HeLa and SGC-7901 cells were determined by SRB method. The data indicated that most of the β-elemene methyl esters of amino acids derivatives show higher proliferation-restraining activities in vitro than that of β-elemene, and the β-elemene amino acid derivatives except 6f, have lower proliferation-re- straining activities. In vivo, compound 5h showed potent inhibitory effects on Lewis lung carcinoma（ ED50 = 35.55 mg.kg-1 ） and H22 hepatoma（ED50 =48.08 mg.kg-1 ） in mice.

关 键 词：Β-榄香烯 β-榄香烯氨基酸衍生物 抗肿瘤活性 

分 类 号：R914[医药卫生—药物化学]