救必应酸衍生物的合成及抗肿瘤活性分析
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摘要
目的:设计、合成以救必应酸(rotundic acid)为母核,引入芳香酯类基团的系列救必应酸衍生物,测试其抑制肿瘤细胞增殖活性,探讨救必应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救必应酸衍生物。方法:以救必应酸为起始原料,通过28位酯化,3β位和23位二芳香酯化反应合成目标化合物1～8。以人恶性黑色素瘤细胞(A375),人宫颈癌细胞(He La),人肺腺癌细胞(SPC-A1),人肝癌细胞(Hep G2)为靶细胞,采用噻唑蓝(MTT)法对所合成的化合物进行体外抗肿瘤活性评价。结果:化合物2～8共7个救必应酸衍生物均为新化合物,其结构经熔点(MP),高分辨质谱(HR-ESI-MS),核磁共振氢谱(~1H-NMR),核磁共振碳谱(~(13)C-NMR)表征均为目标化合物。MTT实验结果表明化合物3,5和8均具有显著的抗肿瘤活性,特别是化合物5对He La,A375,Hep G2,SPC-A1细胞的半抑制浓度(IC_(50))分别为(5.25±1.08),(5.99±0.88),(3.31±1.89),(5.74±1.78)μmol·L~(-1),救必应酸分别是其的1.92,3.22,3.79,3.72倍。结论:化合物5具有显著的抗肿瘤活性,具有进一步研究、开发抗肿瘤新药的意义。
Objective:To design and synthesize series of rotundic acid derivatives by introducing aromatic ester groups with rotundic acid as the parent nucleus,test their anti-tumor activity in vitro,investigate the structure-activity relationship of rotundic acid derivatives in inhibiting tumor cell proliferation,and obtain the novel rotundic acid derivatives with high anti-tumor activity.Method:Compounds 1-8 were synthesized with rotundic acid as the initial raw material through the 28-etherification,3βand 23di-aromatic esterification eaction.The antitumor activities in vitro were evaluated by MTT assay against A375(human malignant melanoma cells),He La(human cervical cancer cells),SPC-A1(human lung adenocarcinoma cells),and HepG2(human liver cancer cells).Result:Compounds 2-8 were new compounds.Their structures were identified by melting point(MP),high resolution electrospray ionization tandem mass spectrometry(HR-ESI-MS),~1H nuclear magnetic resonance(~1H-NMR)and~(13)C nuclear magnetic resonance(~(13)C-NMR).MTT results showed that compounds 3,5 and 8exhibited significant anti-tumor activity,especially compound 5 was found to have the best inhibition activity on He La,A375,HepG2 and SPC-A1 with IC_(50)values of(5.25±1.08),(5.99±0.88),(3.31±1.89),(5.74±1.78)μmol·L~(-1),1.92,3.22,3.79,3.72 times of that of rotundic acid,respectively.Conclusion:Compound 5 has significant anti-tumor activity with great significance for further research and development of new anti-tumor medicines.
Objective:To design and synthesize series of rotundic acid derivatives by introducing aromatic ester groups with rotundic acid as the parent nucleus,test their anti-tumor activity in vitro,investigate the structure-activity relationship of rotundic acid derivatives in inhibiting tumor cell proliferation,and obtain the novel rotundic acid derivatives with high anti-tumor activity.Method:Compounds 1-8 were synthesized with rotundic acid as the initial raw material through the 28-etherification,3βand 23di-aromatic esterification eaction.The antitumor activities in vitro were evaluated by MTT assay against A375(human malignant melanoma cells),He La(human cervical cancer cells),SPC-A1(human lung adenocarcinoma cells),and HepG2(human liver cancer cells).Result:Compounds 2-8 were new compounds.Their structures were identified by melting point(MP),high resolution electrospray ionization tandem mass spectrometry(HR-ESI-MS),~1H nuclear magnetic resonance(~1H-NMR)and~(13)C nuclear magnetic resonance(~(13)C-NMR).MTT results showed that compounds 3,5 and 8exhibited significant anti-tumor activity,especially compound 5 was found to have the best inhibition activity on He La,A375,HepG2 and SPC-A1 with IC_(50)values of(5.25±1.08),(5.99±0.88),(3.31±1.89),(5.74±1.78)μmol·L~(-1),1.92,3.22,3.79,3.72 times of that of rotundic acid,respectively.Conclusion:Compound 5 has significant anti-tumor activity with great significance for further research and development of new anti-tumor medicines.
引文
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[11]HE Y F,NAN M L,SUN J M,et al. Synthesis,characterization and cytotoxicity of new rotundic acid derivatives[J]. Molecules,2012,17(2):1278-1291.
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[13]陈荣,廖晓峰.熊果酸酯的合成研究[J].现代食品科技,2006,22(4):181-182.
[14]林锦璇,王鹏龙,褚福浩,等.新型姜黄素衍生物的合成及其抗癌活性研究[J].中国实验方剂学杂志,2014,20(7):113-117.
[15]范昊宁,佟丽,范钦.姜黄素对肿瘤的抑制和放射增敏作用研究进展[J].中国实验方剂学杂志,2013,19(3):333-335.
[2]解军波,毕志明,李萍. HPLC-ELSD法测定四季青中三萜及其皂苷的含量[J].药学学报,2003,38(7):534-536.
[3]Haraguchi H,Kataoka S,Okamoto S,et al. Antimicrobial triterpenes from Ilex integra and the mechanism of antifungal action[J]. Phytother Res,2015,13(2):151-156.
[4]赵立春.响应曲面法用于救必应等三种药材高效提取及其提取物的药理活性研究[D].保定:河北大学,2013.
[5]刘国樵.五环三萜皂苷化合物的用途:中国,CN101342186[P]. 2009-01-14.
[6]赵全成,南敏伦,赫玉芳,等.救必应酸在制备防治心脑血管疾病的药物中的应用:中国,CN101856357A[P]. 2010-10-13.
[7]贺兴隆.齐墩果酸衍生物的合成与表征及其抑菌活性的研究[D].大连:辽宁师范大学,2011.
[8]刘玲,赵建龙,王建刚.齐墩果酸诱导人肝癌Bel-7402细胞G2/M期阻滞及凋亡的机制研究[J].中国中药杂志,2015,40(24):4897-4902.
[9]杨定菊,李颖,尹述凡. 3-O-乙酰基熊果酸-3-乙酰基-2-[(未)取代苯基]-2,3-二氢-1,3,4-噁二唑-5-甲酯的合成及其抗炎活性研究[J].有机化学,2008,28(6):1055-1060.
[10]倪明宇,马莉,吴英良,等.桦木酸的抗肿瘤作用及其诱导KB细胞凋亡的研究[J].沈阳药科大学学报,2006,23(1):38-42.
[11]HE Y F,NAN M L,SUN J M,et al. Synthesis,characterization and cytotoxicity of new rotundic acid derivatives[J]. Molecules,2012,17(2):1278-1291.
[12]HE Y F,NAN M L,SUN J M,et al. Design,synthesis and cytotoxicity of cell death mechanism of rotundic acid derivatives[J]. Bioorg Med Chem Lett,2013,23(9):2543-2547.
[13]陈荣,廖晓峰.熊果酸酯的合成研究[J].现代食品科技,2006,22(4):181-182.
[14]林锦璇,王鹏龙,褚福浩,等.新型姜黄素衍生物的合成及其抗癌活性研究[J].中国实验方剂学杂志,2014,20(7):113-117.
[15]范昊宁,佟丽,范钦.姜黄素对肿瘤的抑制和放射增敏作用研究进展[J].中国实验方剂学杂志,2013,19(3):333-335.