[1]金晓燕,陈浩,陶徐兵,等.新型熊果酸喹啉衍生物的合成及抗肿瘤活性[J].林业工程学报,2018,3(01):54-64.[doi:10.13360/j.issn.2096-1359.2018.01.010]
 JIN Xiaoyan,CHEN Hao,TAO Xubing,et al.Synthesis and antitumor activity of novel quinoline derivatives of ursolic acid[J].Journal of Forestry Engineering,2018,3(01):54-64.[doi:10.13360/j.issn.2096-1359.2018.01.010]
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新型熊果酸喹啉衍生物的合成及抗肿瘤活性()
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《林业工程学报》[ISSN:1001-8081/CN:32-1160/S]

卷:
3
期数:
2018年01期
页码:
54-64
栏目:
林产化学加工
出版日期:
2018-01-15

文章信息/Info

Title:
Synthesis and antitumor activity of novel quinoline derivatives of ursolic acid
文章编号:
2096-1359(2018)01-0054-11
作者:
金晓燕陈浩陶徐兵王石发谷文*
南京林业大学化学工程学院,江苏省高校农林生物质化学与利用国家重点实验室培育点,江苏省生物质绿色燃料与化学品重点实验室,南京 210037
Author(s):
JIN Xiaoyan CHEN Hao TAO Xubing WANG Shifa GU Wen*
College of Chemical Engineering, Nanjing Forestry University;
Jiangsu Provincial Key Lab for the Chemistry and Utilization of Agro-forest Biomass;
Jiangsu Key Lab of Biomass-based Green Fuels and Chemicals, Nanjing 210037, China
关键词:
熊果酸 喹啉 酰肼 134-噁二唑 抗肿瘤活性
Keywords:
ursolic acid quinoline hydrazide 134-oxadiazole antitumor activity
分类号:
R318.01
DOI:
10.13360/j.issn.2096-1359.2018.01.010
文献标志码:
A
摘要:
以自然界中广泛存在的五环三萜类天然产物熊果酸为原料合成了一系列新型的熊果酸喹啉酰肼衍生物3a~3f和1,3,4-噁二唑衍生物4a~4f。采用1H NMR、13C NMR、IR、ESI-MS、元素分析等方法对化合物3a~3f和4a~4f进行结构表征和分析。通过MTT法测试了化合物3a~3f和4a~4f对MDA-MB-231、HeLa和SMMC-7721 3种肿瘤细胞株的增殖抑制活性。结果表明:化合物3a~3c对所测试3种细胞株均表现出显著的抑制活性。其中,化合物3a~3c对MDA-MB-231细胞的IC50值为1.16~1.84 μM,对HeLa的IC50值为0.83~1.18 μM,对SMMC-7721的IC50值为17.48~19.41 μM,强于阳性对照依托泊苷。根据抗肿瘤活性结果,初步分析化合物的抗肿瘤构效关系,发现在熊果酸分子中引入喹啉基并将羧基修饰为酰肼基和1,3,4-噁二唑基能够显著增强其抗肿瘤活性,且侧链为酰肼的衍生物活性优于噁二唑的衍生物。这一结果可为今后熊果酸的进一步结构优化,寻找具有更强抗肿瘤活性的衍生物提供依据。
Abstract:
A series of novel quinoline derivatives of ursolic acid(3a-3f, 4a-4f)bearing hydrazide and 1,3,4-oxadiazole moieties were synthesized by using ursolic acid, a kind of pentacyclic triterpenoid compounds, as the starting material. The structures of compounds 3a-3f and 4a-4f were characterized by IR, ESI-MS, NMR and elemental analysis. The antitumor activities of compounds 3a-3f and 4a-4f against MDA-MB-231, HeLa and SMMC-7721 cell lines were evaluated by MTT method. The resutls showed that compounds 3a-3c displayed significant antiproliferative activity. The IC50 values of compounds 3a-3c against MDA-MB-231, HeLa and SMMC-7721 cell lines were 1.16-1.84 μM, 0.83-1.18 μM and 17.48-19.41 μM, respectively, which were stronger than those of the positive control etoposide. According to the antitumor activity results, the antitumor structure-activity relationship of the compounds was preliminary analyzed. It was found that the incorporation of quinolinyl groups into the ursolic acid molecule and the modification of the carboxyl group into hydrazide groups and 1,3,4-oxadiazolyl groups could significantly enhance the antitumor activity of the ursolic acid, and that the activities of hydrazide derivatives were superior to the oxadiazole derivatives. The results of this study would provide substantial basis for the future structure modification of ursolic acid and the screening for derivatives with better antitumor activities.

参考文献/References:

[1] 王鹏,张忠义,吴忠. 熊果酸在药用植物中的分布及药理作用[J]. 中药材,2000,23(11):717-722.
[2] ZERIN T,LEE M,JANG W S,et al. Ursolic acid reduces mycobacterium tuberculosis-induced nitric oxide release in human alveolar A549 cells[J]. Molecular Cells,2015,38(7):610-615.
[3] HUSSAIN H, GREEN I R, ALI I, et al. Ursolic acid derivatives for pharmaceutical use: a patent review[J]. Expert Opinion on Therapeutic Patents, 2017, 27(9): 1061-1072.
[4] FU H J,ZHOU Y R,BAO B H,et al. Tryptophan hydroxylase 1(Tph-1)-targeted bone anabolic agents for osteoporosis[J]. Journal of Medicinal Chemistry,2014,57(11):4692-4709.
[5] DAR B A,LONE A M,SHAH W A,et al. Synthesis and screening of ursolic acid-benzylidine derivatives as potential anti-cancer agents[J]. European Journal of Medicinal Chemistry,2016,111:26-32.
[6] RASHID S,DAR B A,MAJEED R,et al. Synthesis and biological evaluation of ursolic acid-triazolyl derivatives as potential anti-cancer agents[J]. European Journal of Medicinal Chemistry,2013,66(66C):238-245.
[7] GU W,HAO Y,ZHANG G,et al. Synthesis, in vitro antimicrobial and cytotoxic activities of new carbazole derivatives of ursolic acid[J]. Bioorganic & Medicinal Chemistry Letters,2015,25(3):554-557.
[8] NARWAL S, KUMAR S, VERMA P K. Synthesis and therapeutic potential of quinoline derivatives[J]. Research on Chemical Intermediates, 2017, 43(5): 2765-2798.
[9] HUSSAINI S M A. Therapeutic significance of quinolines: a patent review(2013-2015)[J]. Expert Opinion on Therapeutic Patents, 2016, 26(10): 1201-1221.
[10] 陈梦涵,杨鸣华,孔令义. 喜树碱类药物的研究与开发[J]. 世界科学技术-中医药现代化,2016,18(5):724-730.
CHEN M H, YANG M H, KONG L Y. Research progress and development of camptothecin derivatives[J]. World Science and Technology-Modernization of Traditional Chinese Medicine,2016,18(5):724-730.
[11] 瘙 塁 ENKARDE 瘙 塁 S,KAUSHIK-BASU N,DURMAZ Í,et al. Synthesis of novel diflunisal hydrazide-hydrazones as anti-hepatitis C virus agents and hepatocellular carcinoma inhibitors[J]. European Journal of Medicinal Chemistry,2016,108:301-308.
[12] PARK E B, KIM K J, JEONG H R, et al. Synthesis, structural determination, and biological evaluation of phenylsulfonyl hydrazide derivatives as potential anti-inflammatory agents[J]. Bioorganic Medicinal Chemistry Letters, 2016, 26(21): 5193-5197.
[13] MUKHERJEE D D,KUMAR N M,TANTAK M P,et al. Development of novel Bis(indolyl)-hydrazide-hydrazone derivatives as potent microtubule-targeting cytotoxic agents against a549 lung cancer cells[J]. Biochemistry,2016,55(21):3020-3035.
[14] IYER V B,GURUPADAYYA B,KOGANTI V S,et al. Design, synthesis and biological evaluation of 1,3,4-oxadiazoles as promising anti-inflammatory agents[J]. Medicinal Chemistry Research,2017,26(1):190-204.
[15] TIWARI A,KUTTY G N,KUMAR N,et al. Synthesis and evaluation of selected 1,3,4-oxadiazole derivatives for in vitro cytotoxicity and in vivo anti-tumor activity[J]. Cytotechnology,2016,68(6):2553-2565.
[16] CARUSO B C,NIKOLIC D,MARINO G A,et al. The dissociation of the Hsp60/pro-Caspase-3 complex by bis(pyridyl)oxadiazole copper complex(CubipyOXA)leads to cell death in NCI-H292 cancer cells[J]. Journal of Inorganic Biochemistry,2017,170:8-16.

备注/Memo

备注/Memo:
收稿日期:2017-04-26 修回日期:2017-06-22
基金项目:江苏省自然科学基金(BK201516); 江苏省绿色燃料与化学品重点实验室开放基金(JSBGFC14008); 江苏省普通高校研究生科研创新计划项目(KYL15-089)。
作者简介:金晓燕,女,研究方向为天然产物合成与利用。通信作者:谷文,男,副教授。E-mail:njguwen@163.com。
更新日期/Last Update: 2018-01-10