藤黄酸氰基衍生物的合成及抗肿瘤活性

doi:10.11944/j.issn.1000-0518.2016.08.150397

摘要/Abstract

摘要：

以藤黄酸为原料,经过酯化反应或酰胺化反应,在C-30位的羧基上引入不同的烷氰基或芳香氰基,设计合成了7个藤黄酸氰基衍生物,其中6个为新化合物,其结构经MS和¹H NMR确证。采用四氮唑蓝(MTT)法测试了合成化合物对肝癌细胞(HepG2)、结肠腺癌细胞(RKO)和卵巢腺癌细胞(OVCAR-3)的体外抗肿瘤活性,结果表明,所合成的化合物均具有一定的抗肿瘤活性,其中化合物4和6的抗肿瘤活性明显优于阳性对照物藤黄酸。

关键词: 藤黄酸, 氰基, 合成, 抗肿瘤, 衍生物

Abstract:

Seven nitrile-containing gambogic acid derivatives were synthesized from gambogic acid(GA) through introducing different alkylnitriles or arylnitriles on the C-30 carboxyl of gambogic acid. Six of them are new compounds(1~6). Their structures were identified by ¹H NMR and MS analysis. The evaluation of antitumor bioactivities in vitro on the hepatoma cells(HepG2), colon adenocarcinoma cells(RKO) and ovarian adenocarcinoma cells(OVCAR-3) were done by the methylthiazolydiphenyl-tetrazolium bromide(MTT) method. The results show that most of the synthesized compounds have strong antitumor activities. Among them, the antitumor activities of compounds 4 and 6 are more potent than that of gambogic acid.

Key words: gambogic acid, cyano group, synthesis, antitumor, derivative

陈美君, 黎金海, 张志佳, 廖思燕, 黄雁, 谭茵. 藤黄酸氰基衍生物的合成及抗肿瘤活性[J]. 应用化学, 2016, 33(8): 905-912.

CHEN Meijun, LI Jinhai, ZHANG Zhijia, LIAO Siyan, HUANG Yan, TAN Yin. Synthesis and Anti-tumor Evaluation of Nitrile-Containing Gambogic Acid Derivatives[J]. Chinese Journal of Applied Chemistry, 2016, 33(8): 905-912.

参考文献

[1]	YANG Jing,DING Li,LIU Wenyuan,et al.Recent Advances in Chemistry and Biology of Gamboge[J]. China J Chinese Mater Med,2013,38(1):19-25(in Chinese). 杨靖,丁黎,柳文嫒,等. 藤黄化学生物学研究进展[J]. 中国中药杂志,2013,38(1):19-25.
[2]	Liesenklas W,Auterhoff H. The Constitution of Gambogic Acid and its Isomerization.4 Chemistry of Gum-resin[J]. Arch Pharm Ber Dtsch Pharm Ges,1966,299(9):797-798.
[3]	Wang X,Lu N,Yang Q,et al.Studies on Chemical Modification and Biology of a Natural Product, Gambogic Acid(Ⅲ):Determination of the Essential Pharmacophore for Biological Activity[J]. Eur J Med Chem,2011,46(4):1280-1290.
[4]	Duan D,Zhang B,Yao J,et al.Gambogic Acid Induces Apoptosis in Hepatocellular Carcinoma SMMC-7721 Cells by Targeting Cytosolic Thioredoxin Reductase[J]. Free Radic Biol Med,2014,69(4):15-25.
[5]	Shi X,Chen X,Li X,et al.Gambogic Acid Induces Apoptosis in Imatinib-resistant Chronic Myeloid Leukemia Cells via Inducing Proteasome Inhibition and Caspase-dependent Bcr-Abl downreg-ulation[J]. Clin Cancer Res,2014,20(1):151-163.
[6]	Wang L H,Yang J Y,Yang S N,et al.Suppression of NF-κB Signaling and P-Glycoprotein Function by Gambogic Acid Synergistically Potentiates Adriamycin-induced Apoptosis in Lung Cancer[J]. Curr Cancer Drug Targets,2014,14(1):91-103.
[7]	Chi Y,Zhan X K,Yu H,et al.An Open-labeled, Randomized, Multicenter PhaseⅡa Study of Gambogic Acid Injection for Advanced Malignant Tumors[J]. Chinese Med J(Engl),2013,126(9):1642-1646.
[8]	A Krajarng,M Imoto,E Tashiro,et al.Apoptosis Induction Associated with the ER Stress Response through Up-regulation of JNK in Hela Cells by Gambogic Acid[J]. BMC Compl Alternat Med,2015,15(1):1-9.
[9]	Mohammad Ishaq,Mohammad Aslam Khan,Kapil Sharma,et al.Gambogic Acid Induced Oxidative Stress Dependent Caspase Activation Regulates both Apoptosis and Autophagy by Targeting Various Key Molecules(NF-κB, Beclin-1, p62 and NBR1) in Human Bladder Cancer Cells[J]. Biochim Biophys Acta(BBA)-Gen Sub,2014,1840(12):3374-3384.
[10]	Huang H,Chen D,Li S,et al.Gambogic Acid Enhances Proteasome Inhibitor-induced Anticancer Activity[J]. Cancer Lett,2011,301(2):221-228.
[11]	Zhao Q,Yang Y,Yu J,et al.Posttranscriptional Regulation of the Telomerase hTERT by Gambogic Acid in Human Gastric Carcinoma 823 Cells[J]. Cancer Lett,2008,262(2):223-231.
[12]	Pandey M K,Sung B,Ahn K S,et al.Gambogic Acid, a Novel Ligand for Transferrin Receptor, Potentiates TNF-induced Apoptosis Through Modulation of the Nuclear Factor-κB Signaling Pathway[J]. Blood,2007,110(10):3517-3525.
[13]	QIAN Jing,WANG Keming. Progress in the Effect of Anti-tumor Molecular Targets of Gambogic Acid[J]. China Cancer,2011,20(6):441-446(in Chinese). 钱婧,王科明. 藤黄酸抗肿瘤作用靶点的研究进展[J]. 中国肿瘤,2011,20(6):441-446.
[14]	Gupta S C,Kim J H,Prasad S,et al.Regulation of Survival, Proliferation, Invasion, Angiogenesis, and Metastasis of Tumor Cells through Modulation of Inflammatory Pathways by Nutraceuticals[J]. Cancer Metast Rev,2010,29(3):405-434.
[15]	Fleming F F,Yao L H,Ravikumar P C,et al.Nitrile-Containing Pharmaceuticals:Efficacious Roles of the Nitrile Pharmacophore[J]. J Med Chem,2010,53(22):7902-7917.
[16]	WANG Jiang,LIU Hong. Application of Nitrile in Drug Design[J]. Chinese J Org Chem,2012,32(9):1643-1652(in Chinese). 王江,柳红. 氰基在药物分子设计中的应用[J]. 有机化学,2012,32(9):1643-1652.
[17]	ZHAO Shengyin,HUANG Wenlong. Synthesis and Vasorelaxant Activity of Trans-3-hydroxy-4-aminobenzopyran Acetylated Derivatives as K+ Channel Openers[J]. Chinese J Appl Chem,2007,24(6):698-702(in Chinese). 赵圣印,黄文龙. 反式-3-羟基-4-胺基苯并吡喃乙酰化物的合成及其血管舒张活性[J]. 应用化学,2007,24(6):698-702.
[18]	Pascual E,Sivera F,Yasothan U,et al.Febuxostat[J]. Nat Rev Drug Discovery,2009,8(3):191-192.
[19]	Fradet Y. Bicalutamide(Casodex) in the Treatment of Prostate Cancer[J]. Expert Rev Anticancer Ther,2004,4(1):37-48.
[20]	ZHANG Shenglie,LI Qian,ZHANG Lei,et al.Synthesis and Bioevaluation of Gambogic Acid Derivatives as Antitumor Agents[J]. Chinese J Org Chem,2012,32(8):1450-1458(in Chinese). 张生烈,李乾,张磊,等. 藤黄酸衍生物的合成及抗肿瘤活性研究[J]. 有机化学,2012,32(8):1450-1458.
[21]	HE Liqin,WU Yaxian,FU Li,et al.Synthesis and Biological Evaluation of Aminoalcohol Gambogate as Anti-tumor Agents[J]. J China Pharm Univ,2013,44(5):394-400(in Chinese). 何黎琴,吴亚先,付俐,等. 藤黄酸胺基醇酯的合成及其抗肿瘤活性[J]. 中国药科大学学报,2013,44(5):394-400.
[22]	Wang J X,Zhang B H,You Q D,et al.Synthesis and Anti-tumor Activity of NO-donating Derivatives of Gambogic Acid[J]. Chinese J Nat Med,2013,11(1):87-96.
[23]	He L,Ling Y,Fu L,et al.Synthesis and Biological Evaluation of Novel Derivatives of Gambogic Acid as Anti-hepatocellular Carcinoma Agents[J]. Bioorg Med Chem Lett,2012,22(1):289-292.
[24]	Ahmad S A,Rigby W,Taylor R B. Gamboge. Part Ⅱ[J]. J Chem Soc C,1996:772-779.