广西师范大学学报（自然科学版） ›› 2021, Vol. 39 ›› Issue (2): 132-138.doi: 10.16088/j.issn.1001-6600.2020011603

• CCIR2020 • 上一篇    下一篇

齐墩果酸-对羟基苯甲腈及其类似物的合成与抗肿瘤活性评价

刘晶晶1,2, 陈转欣1,2, 尤佳航1,2, 黄家艳1,2, 程克光1,2*   

  1. 1.省部共建药用资源化学与药物分子工程国家重点实验室广西师范大学, 广西 桂林541004;
    2.广西师范大学 化学与药学学院, 广西 桂林541004
  • 收稿日期:2020-01-16 修回日期:2020-03-03 出版日期:2021-03-25 发布日期:2021-04-15
  • 通讯作者: 程克光(1983—),女,湖北荆州人,广西师范大学教授,博士。E-mail:kgcheng2008@gmail.com
  • 基金资助:
    国家自然科学基金(21562006);广西自然科学基金(2015GXNSFAA139186);广西医药产业人才小高地项目(1506);药用资源化学与药物分子工程教育部重点实验室资助课题(CMEMR2013-A01,CMEMR2013-C02)

Synthesis and Antitumor Activity Evaluation of Oleanolic Acid-p-hydroxybenzonitrile and Its Analogues

LIU Jingjing1,2, CHEN Zhuanxin1,2, YOU Jiahang1,2, HUANG Jiayan1,2, CHENG Keguang1,2*   

  1. 1. State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources Guangxi Normal University, Guilin Guangxi 541004, China;
    2. School of Chemistry and Pharmacy, Guangxi Normal University, Guilin Guangxi 541004, China
  • Received:2020-01-16 Revised:2020-03-03 Online:2021-03-25 Published:2021-04-15

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摘要： 以齐墩果酸、熊果酸和甘草次酸为原料,在碱性条件下,与二溴烷烃反应生成溴代烷烃酯;继而与对羟基苯甲腈发生亲核取代反应,共合成得到6个齐墩果酸/熊果酸/甘草次酸-对羟基苯甲腈缀合物,并采用MTT法测试其抗肿瘤活性。结果显示:[(4-氰基苯氧基)-正己基]-甘草次酸酯和[(4-氰基苯氧基)-正辛基]-甘草次酸酯对慢性髓系白血病细胞系K562有一定的抗增殖作用,其中[(4-氰基苯氧基)-正己基]-甘草次酸酯对人肝肿瘤细胞系Bel-7402也有中等抗增殖作用,其余化合物对所测细胞都没有抗增殖活性。[(4-氰基苯氧基)-正己基]-甘草次酸酯对测试细胞的抗增殖活性与阳性对照药5-FU相当,对正常肝细胞损伤较少,具有进一步研究的潜在价值。

关键词: 齐墩果酸, 熊果酸, 甘草次酸, 对羟基苯甲腈, 抗肿瘤活性

Abstract: Oleanolic acid, ursolic acid and glycyrrhetinic acid were esterified with corresponding α,ω-dibromoalkane in the presence of potassium carbonate to prepare intermediates. Then, the intermediates were treated with p-hydroxybenzonitrile under potassium carbonate by means of a nucleophilic substitution reaction to generate six oleanolic acid/ursolic acid/glycyrrhetinic acid-p-hydroxybenzonitrile derivatives. Anti-tumor activity was tested by the MTT assay. The results showed that glycyrrhetinic acid-p-hydroxybenzonitrile conjugates [n-(4-cyanophenoxy)-hexyl]-3β-hydroxy-11-oxo-olean-12-en-29-oate and [n-(4-cyanophenoxy)-octyl]-3β-hydroxy-11-oxo-olean-12-en-29-oate had certain anti-proliferative effect on chronic myeloid leukemia cell line K562. Moreover, [n-(4-cyanophenoxy)-hexyl]-3β-hydroxy-11-oxo-olean-12-en-29-oate also had moderate anti-proliferative effect on human liver tumor cell line Bel-7402. Other compounds had no antiproliferative activity on the tested cell lines. [n-(4-Cyanophenoxy)-hexyl]-3β-hydroxy-11-oxo-olean-12-en-29-oate, which has less damage to normal liver cells, expressed almost the same level as the positive control drug 5-FU on the anti-proliferative activity of the tested cells. This indicated that [n-(4-cyanophenoxy)-hexyl]-3β-hydroxy-11-oxo-olean-12-en-29-oateand had the potential value for further research in anti-tumor field.

Key words: oleanolic acid, ursolic acid, glycyrrhetinic acid, p-hydroxybenzonitrile, antitumor activity

中图分类号: 

  • R914
[1] 种连娥,廖慧敏,王海燕,等.非布索坦的合成工艺研究[J].中国药物化学杂志,2014,24(4):303-306.
[2] 刘小卒,刘培均,袁泽利,等.抗痛风药非布索坦的合成[J].精细化工,2014,31(6):745-748.
[3] 潘洁玉.对羟基苯甲腈生产工艺的研究与开发[D].西安:西北大学,2012.
[4] 刘泽,胡博,李珊,等.4-羟基苯甲腈的合成[J].精细化工中间体,2017,47(1):60-62.
[5] 王勤,邱凌,宋康康,等.对氰基苯酚对蘑菇酪氨酸酶的抑制作用[J].厦门大学学报(自然科学版),2004,43(4):568-571.
[6] 王喆,赵宏涛.羟基苯甲腈类抑制剂与Cdc25B磷酸酯酶相互作用的结合位点残基观察[J].山东医药,2015,55(23):18-20.
[7] LUND G,DUDKIN S,BORKIN D,et al.Inhibition of CDC25B phosphatase through disruption of protein-protein interaction[J].ACS Chemical Biology,2015,10(2):390-394.
[8] 陈晔,丁晨晨,郭志军,等.五环三萜类化合物药理活性研究进展[J].武警后勤学院学报(医学版),2017,26(12):1083-1087.
[9] ZHU M,DU X N,LI Y G,et al.Design,synthesis and biological evaluation of novel HIV-1 protease inhibitors with pentacyclic triterpenoids as P2-ligands[J].Bioorganic and Medicinal Chemistry Letters,2019,29(3):357-361.
[10] 刘蒲,王国权.五环三萜类化合物的药理作用研究进展[J].海峡药学,2018,30(10):1-6.
[11] SALVADOR J A R,LEAL A S,VALDEIRA A S,et al.Oleanane-,ursane-,and quinone methide friedelane-type triterpenoid derivatives:Recent advances in cancer treatment[J].European Journal of Medicinal Chemistry,2017,142:95-130.
[12] WANG H Z,ZHONG W L,ZHAO J M,et al.Oleanolic acid inhibits epithelial-mesenchymal transition of hepatocellular carcinoma by promoting iNOS dimerization[J].Molecular Cancer Therapeutics,2019,18(1):62-74.
[13] 张明发,沈雅琴.熊果酸和齐墩果酸抗脑瘤作用的研究进展[J].药物评价研究,2016,39(1):132-135.
[14] GUO J L,HAN T,BAO L,et al.Ursolic acid promotes the apoptosis of cervical cancer cells by regulating endoplasmic reticulum stress[J].Journal of Obstetrics and Gynaecology Research,2019,45(4):877-881.
[15] CHEN J,ZHANG Z Q,SONG J,et al.18β-Glycyrrhetinic-acid-mediated unfolded protein response induces autophagy and apoptosis in hepatocellular carcinoma[J].Scientific Reports,2018,8:9365.
[16] WANG S S,SHEN Y,QIU R F,et al.18β-glycyrrhetinic acid exhibits potent antitumor effects against colorectal cancer via inhibition of cell proliferation and migration[J].International Journal of Oncology,2017,51(2):615-624.
[17] SPIVAK A,KHALITOVA R,NEDOPEKINA D,et al.Synthesis and evaluation of anticancer activities of novel C-28 guanidine-functionalized triterpene acid derivatives[J].Molecules,2018,23(11):3000.
[18] WANG R,LI Y,HUAI X D,et al.Design and preparation of derivatives of oleanolic and glycyrrhetinic acids with cytotoxic properties[J].Drug Design Development and Therapy,2018,12:1321-1336.
[19] LIN Y Y,CHAN S H,JUANG Y P,et al.Design,synthesis and cytotoxic activity of N-modified oleanolic saponins bearing a glucosamine[J].European Journal of Medicinal Chemistry,2018,143:1942-1958.
[20] CHEN Y H,HOU X Y,ZHI D F,et al.Synthesis,characterization and anticancer activity of oleanolic acid and ursolic acid derivatives[J].Chinese Journal of Organic Chemistry,2016,36(4):795-802.
[21] WANG W Z,LEI L,LIU Z,et al.Design,synthesis,and biological evaluation of novel nitrogen heterocycle-containing ursolic acid analogs as antitumor agents[J].Molecules,2019,24(5):877.
[22] SUN H,YUE P Y K,WANG S R,et al.Synthesis and biological evaluations of cytotoxic and antiangiogenic triterpenoids-jacaranone conjugates[J].Medicinal Chemistry (Sharjah,United Arab Emirates),2016,12(8):775-785.
[23] JIN L,DAI L M,JI M,et al.Mitochondria-targeted triphenylphosphonium conjugated glycyrrhetinic acid derivatives as potent anticancer drugs[J].Bioorganic Chemistry,2019,85:179-190.
[24] JIN L,HUANG R Z,HUANG X C,et al.Discovery of 18β-glycyrrhetinic acid conjugated aminobenzothiazole derivatives as Hsp90-Cdc37 interaction disruptors that inhibit cell migration and reverse drug resistance[J].Bioorganic and Medicinal Chemistry,2018,26(8):1759-1775.
[25] 孙立,初相伍,刘春梅,等.熊果酸/甘草次酸-尿嘧啶核苷缀合物的合成与抗肿瘤活性评价[J].广西师范大学学报(自然科学版),2020,38(1):87-92.
[26] CHENG K G,SU C H,YANG L D,et al.Synthesis of oleanolic acid dimers linked at C-28 and evaluation of anti-tumor activity[J].European Journal of Medicinal Chemistry,2015,89:480-489.
[27] CHENG K G,SU C H,HUANG J Y,et al.Synthesis and cytotoxic evaluation of several oleanolic acid-uracil/thymine conjugates[J].Medicinal Chemistry Communication,2016,7(5):972-981.
[28] CHENG K G,SU C H,HUANG J Y,et al.Conjugation of uridine with oleanolic acid derivatives as potential antitumor agents[J].Chemical Biology and Drug Design,2016,88(3):329-340.
[29] MALLAVADHANI U V,MAHAPATRA A,PATTNAIK B,et al.Synthesis and anti-cancer activity of some novel C-17 analogs of ursolic and oleanolic acids[J].Medicinal Chemistry Research,2013,22(3):1263-1269.
[30] HUANG J Y,YANG L D,SU C H,et al.Synthesis and cytotoxicity evaluation of pentacyclic triterpene-phenol nitrogen mustard conjugates[J].Chemistry of Natural Compounds,2018,54(1):106-111.
[31] SCHWARZ S,LUCAS S D,SOMMERWERK S,et al.Amino derivatives of glycyrrhetinic acid as potential inhibitors of cholinesterases[J].Bioorganic and Medicinal Chemistry,2014,22(13):3370-3378.
[32] MOSMANN T.Rapid colorimetric assay for cellular growth and survival:application to proliferation and cytotoxicity assays[J].Journal of Immunological Methods,1983,65(1/2):55-63.
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