荷叶碱药理作用的研究进展

陈畅; 谢永艳; 黄丽萍

doi:10.14148/j.issn.1672-0482.2021.0619

荷叶碱药理作用的研究进展

doi: 10.14148/j.issn.1672-0482.2021.0619

陈畅^{1, 2,},
谢永艳¹,
黄丽萍^1, ,

1.
江西中医药大学药学院，江西南昌 330004
2.
中国中医科学院中药研究所，北京 100700

基金项目:

国家自然科学基金 82060759

国家自然科学基金 81660713

国家“重大新药创制”科技重大专项 2019ZX09201005

详细信息

作者简介:
陈畅，男，副研究员, E-mail：cchen@icmm.ac.cn

通讯作者:
黄丽萍，女，教授，博士生导师，主要从事中药神经药理学研究, E-mail：jxnchlp@163.com

中图分类号: R285.5
计量
- 文章访问数: 862
- HTML全文浏览量: 214
- PDF下载量: 354
- 被引次数: 0
出版历程
- 收稿日期: 2021-01-25
- 网络出版日期: 2021-12-21
- 刊出日期: 2021-07-10
- 发布日期: 2021-07-15

Advance of Pharmacological Studies on Nuciferine

CHEN Chang^{1, 2
,},
XIE Yong-yan¹,
HUANG Li-ping^{1
, ,}

1.
School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang, 330004, China
2.
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China

摘要

摘要: 荷叶碱是来源于睡莲科植物莲干燥叶中的一种阿朴啡类生物碱，也是《中国药典》收载荷叶这味中药的质控成分。现代研究表明，荷叶碱具有降脂、降糖、抗肿瘤、抗脑缺血等多种药理作用，具有广阔的开发前景。但荷叶碱自身存在水溶性差、药物安全性数据缺失、生物利用度争议较大等成药性缺陷，极大地影响了荷叶碱的深入研究与开发。因此，如何从众多药理活性中获得启发，进而选择最适合荷叶碱产品开发的临床适应症，依据制剂或化学手段改善其溶解性和生物利用度，同时降低毒副作用的发生，是当前迫切需要解决的问题。该文在回顾荷叶碱的理化性质及药动学研究报道的基础上，系统总结了其药理活性及作用机制，以期为荷叶碱药理作用的深入研究及创新品种的开发提供参考。
- 荷叶碱 /
- 药理作用 /
- 机制 /
- 降脂 /
- 抗肿瘤 /
- 降糖
Abstract: Nuciferine is a key aporphine alkaloid in the dried leaves of Nelumbo nucifera Gaertn (LNNG), which is also the quality control component of LNNG in Chinese Pharmacopoeia. It is reported that nuciferine has many pharmacological effects, such as lipid-lowering, anti-hyperglycemia, anti-tumor, anti-cerebral ischemia, and has a broad development prospect. However, there are some medicinal defects, such as poor water solubility, lack of safety data, and controversy of bioavailability, which greatly affect the in-depth research and development of nuciferine. Therefore, how to choose the most suitable clinical indications from massive pharmacological activities, improve its solubility and bioavailability through preparation or chemical method, and reduce the occurrence of toxic and side effects, are urgent to be solved. In this paper, the physicochemical property, pharmacokinetic characteristics, pharmacological activity and underling mechanism of nuciferine were systematically summarized, which can be helpful for the further study of its pharmacological action and the development of innovative products.
- nuciferine /
- pharmacological effect /
- mechanism /
- lipid-lowering /
- anti-tumor /
- anti-hyperglycemia

HTML全文

参考文献(79)

[1]	孟诜. 食疗本草[M]. 尹海德, 评注. 北京: 中华书局, 2011: 71.
[2]	朱怡, 顾联斌. 荷叶临床效用发微[J]. 上海中医药杂志, 2017, 51(6): 77-78. https://www.cnki.com.cn/Article/CJFDTOTAL-SHZZ201706024.htm
[3]	万勇, 林云华, 尹燕耀, 等. 荷叶降脂颗粒对脂肪肝影响的随机双盲对照临床研究[J]. 中华中医药杂志, 2015, 30(8): 3030-3032. https://www.cnki.com.cn/Article/CJFDTOTAL-BXYY201508113.htm
[4]	陈宇基, 何义华. 荷叶降脂汤联合穴位注射改善非酒精性脂肪性肝病胰岛素抵抗随机平行对照研究[J]. 实用中医内科杂志, 2015, 29(10): 85-88. https://www.cnki.com.cn/Article/CJFDTOTAL-SYZY201510045.htm
[5]	杨介智, 杨素友. 荷叶治疗牙痛50例[J]. 人民军医, 1983, 26(3): 74. https://www.cnki.com.cn/Article/CJFDTOTAL-RMJZ198303047.htm
[6]	赵以存. 中药荷叶丸治疗鼻出血40例临床观察[J]. 人民军医, 1961(7): 23. https://www.cnki.com.cn/Article/CJFDTOTAL-RMJZ196107021.htm
[7]	高原. 夏日荷叶食疗保健[J]. 园林, 1998(1): 45. https://www.cnki.com.cn/Article/CJFDTOTAL-YUNI199801041.htm
[8]	远颖, 丁娜, 杨惠. 含荷叶保健食品的用药规律[J]. 中医药导报, 2020, 26(1): 61-65. https://www.cnki.com.cn/Article/CJFDTOTAL-HNZB202001019.htm
[9]	李梢. 荷叶碱和荷叶提取物作为制备治疗萎缩性胃炎和/或阻断胃炎癌转化发生药物的应用: CN110393715A[P]. 2019-11-01.
[10]	孙常磊, 朱丽平, 段朝辉, 等. 荷叶碱或含其的植物提取物的应用: CN102949299B[P]. 2013-03-06.
[11]	赵珺睿, 任晓亮, 王萌. 荷叶药材中荷叶碱生物药剂学分类系统研究[J]. 中国中药杂志, 2018, 43(3): 511-519. https://www.cnki.com.cn/Article/CJFDTOTAL-ZGZY201803013.htm
[12]	WANG LM, WANG P, TEKA T, et al. ¹H NMR and UHPLC/Q-orbitrap-MS-based metabolomics combined with 16S rRNA gut microbiota analysis revealed the potential regulation mechanism of nuciferine in hyperuricemia rats[J]. J Agric Food Chem, 2020, 68(47): 14059-14070. doi: 10.1021/acs.jafc.0c04985
[13]	WU LL, CHEN C, LI YB, et al. UPLC-Q-TOF/MS-based serum metabolomics reveals the anti-ischemic stroke mechanism of nuciferine in MCAO rats[J]. ACS Omega, 2020, 5(51): 33433-33444. doi: 10.1021/acsomega.0c05388
[14]	FARRELL MS, MCCORVY JD, HUANG XP, et al. In vitro and in vivo characterization of the alkaloid nuciferine[J]. PLoS ONE, 2016, 11(3): e0150602. http://europepmc.org/articles/PMC4786259?pdf=render
[15]	YANG X, YU MF, LEI J, et al. Nuciferinerelaxes tracheal rings via the blockade of VDLCC and NSCC channels[J]. Planta Med, 2018, 84(2): 83-90. doi: 10.1055/s-0043-118178
[16]	WANG XF, CHEANG WS, YANG HX, et al. Nuciferine relaxes rat mesenteric arteries through endothelium-dependent and -independent mechanisms[J]. Br J Pharmacol, 2015, 172(23): 5609-5618. doi: 10.1111/bph.13021
[17]	WANG MX, LIU YL, YANG Y, et al. Nuciferine restores potassium oxonate-induced hyperuricemia and kidney inflammation in mice[J]. Eur J Pharmacol, 2015, 747: 59-70. doi: 10.1016/j.ejphar.2014.11.035
[18]	BOUSTIE J, STIGLIANI JL, MONTANHA J, et al. Antipoliovirus structure-activity relationships of some aporphine alkaloids[J]. J Nat Prod, 1998, 61(4): 480-484. doi: 10.1021/np970382v
[19]	KASHIWADA Y, AOSHIMA A, IKESHIRO Y, et al. Anti-HIV benzylisoquinoline alkaloids and flavonoids from the leaves of Nelumbo nucifera, and structure-activity correlations with related alkaloids[J]. Bioorg Med Chem, 2005, 13(2): 443-448. doi: 10.1016/j.bmc.2004.10.020
[20]	NAKAMURA S, NAKASHIMA S, TANABE G, et al. Alkaloid constituents from flower buds and leaves of sacred Lotus (Nelumbo nucifera, Nymphaeaceae) with melanogenesis inhibitory activity in B16 melanoma cells[J]. Bioorg Med Chem, 2013, 21(3): 779-787. doi: 10.1016/j.bmc.2012.11.038
[21]	ZHANG DD, ZHANG JG, WU X, et al. Nuciferine downregulates Per-Arnt-Sim kinase expression during its alleviation of lipogenesis and inflammation on oleic acid-induced hepatic steatosis in HepG2 cells[J]. Front Pharmacol, 2015, 6: 238. http://pubmedcentralcanada.ca/pmcc/articles/PMC4612658/
[22]	LI ZZ, CHEN YD, AN TT, et al. Nuciferine inhibits the progression of glioblastoma by suppressing the SOX2-AKT/STAT3-Slug signaling pathway[J]. J Exp Clin Cancer Res, 2019, 38(1): 139. doi: 10.1186/s13046-019-1134-y
[23]	QI Q, LI R, LI HY, et al. Identification of the anti-tumor activity and mechanisms of nuciferine through a network pharmacology approach[J]. Acta Pharmacol Sin, 2016, 37(7): 963-972. doi: 10.1038/aps.2016.53
[24]	KANG EJ, LEE SK, PARK KK, et al. Liensinine andnuciferine, bioactive components of Nelumbo nucifera, inhibit the growth of breast cancer cells and breast cancer-associated bone loss[J]. Evid Based Complement Alternat Med, 2017, 2017: 1583185. http://www.ncbi.nlm.nih.gov/pubmed/29333179
[25]	YE LH, HE XX, YOU C, et al. Pharmacokinetics ofnuciferine and N-nornuciferine, two major alkaloids from Nelumbo nucifera leaves, in rat plasma and the brain[J]. Front Pharmacol, 2018, 9: 902. doi: 10.3389/fphar.2018.00902
[26]	GU SY, ZHU GH, WANG YZ, et al. A sensitive liquid chromatography-tandem mass spectrometry method for pharmacokinetics and tissue distribution of nuciferine in rats[J]. J Chromatogr B Analyt Technol Biomed Life Sci, 2014, 961: 20-28. doi: 10.1016/j.jchromb.2014.04.038
[27]	XU YY, BAO SH, TIAN WQ, et al. Tissue distribution model and pharmacokinetics of nuciferine based on UPLC-MS/MS and BP-ANN[J]. Int J Clin Exp Med, 2015, 8(10): 17612-17622. http://pdfs.semanticscholar.org/19da/204c3b16ae913c6c1169be42b593a61f0051.pdf
[28]	谢水林, 王翌尧, 谭玉溪, 等. 荷叶碱在大鼠体内的绝对生物利用度研究[J]. 广东药学院学报, 2010, 26(1): 17-19. doi: 10.3969/j.issn.1006-8783.2010.01.005
[29]	WANG FG, CAO J, HOU XQ, et al. Pharmacokinetics, tissue distribution, bioavailability, and excretion of nuciferine, an alkaloid from lotus, in rats by LC/MS/MS[J]. Drug Dev Ind Pharm, 2018, 44(9): 1557-1562. doi: 10.1080/03639045.2018.1483399
[30]	YE LH, XIAO BX, LIAO YH, et al. Metabolism profiles of nuciferine in rats using ultrafast liquid chromatography with tandem mass spectrometry[J]. Biomed Chromatogr, 2016, 30(8): 1216-1222. doi: 10.1002/bmc.3670
[31]	WU XL, WU MJ, CHEN XZ, et al. Metabolic profiling of nuciferine in rat urine, plasma, bile and feces after oral administration using ultra-high performance liquid chromatography-diode array detection-quadrupole time-of-flight mass spectrometry[J]. J Pharm Biomed Anal, 2017, 140: 71-80. doi: 10.1016/j.jpba.2017.03.022
[32]	GAO H, ZHANG L, ZHU A, et al. Metabolicprofiling of nuciferine in vivo and in vitro[J]. J Agric Food Chem, 2020, 68(48): 14135-14147. doi: 10.1021/acs.jafc.0c04468
[33]	李时珍. 本草纲目: 下册[M]. 北京: 人民卫生出版社, 2004: 1899.
[34]	熊万涛, 廖加抱, 杨智霞, 等. 荷叶碱对肥胖模型小鼠肠道菌群及慢性炎症的影响[J/OL]. 中国中药杂志, 2020. DOI: 10.19540/j.cnki.cjcmm.20201207.401.
[35]	谢斌. 一种制剂处方筛选评价方法的建立与荷叶碱对大鼠3T3-L1前脂肪细胞分化的影响[D]. 武汉: 华中科技大学, 2011.
[36]	何冰, 高雁鸿, 孙华, 等. 荷叶碱对非酒精性脂肪肝模型小鼠肝组织中SREBP信号通路的影响[J]. 天津中医药大学学报, 2020, 39(3): 320-323. https://www.cnki.com.cn/Article/CJFDTOTAL-TZYY202003019.htm
[37]	GUO F, YANG X, LI X, et al. Nuciferine prevents hepatic steatosis and injury induced by a high-fat diet in hamsters[J]. PLoS ONE, 2013, 8(5): e63770. http://europepmc.org/articles/PMC3655021/pdf/pone.0063770.pdf
[38]	YU Y, LU J, SUN L, et al. Akkermansia muciniphila: A potential novel mechanism of nuciferine to improve hyperlipidemia[J]. Biomedecine Pharmacother, 2021, 133: 111014. doi: 10.1016/j.biopha.2020.111014
[39]	CUI HT, LI YT, CAO M, et al. Untargeted metabolomic analysis of the effects and mechanism of nuciferine treatment on rats with nonalcoholic fatty liver disease[J]. Front Pharmacol, 2020, 11: 858. doi: 10.3389/fphar.2020.00858
[40]	张丽静, 艾耀伟, 王政强. 荷叶碱防治小鼠高脂血症作用及其机制[J]. 医药导报, 2015, 34(4): 440-444. doi: 10.3870/yydb.2015.04.004
[41]	ZHOU YY, CHEN ZH, LIN QM, et al. Nuciferine reduced fat deposition by controlling triglyceride and cholesterol concentration in broiler chickens[J]. Poult Sci, 2020, 99(12): 7101-7108. doi: 10.1016/j.psj.2020.09.013
[42]	韩晓, 吴成爱, 王伟, 等. 荷叶碱对bel-7402细胞胆固醇代谢的影响[J]. 现代生物医学进展, 2008, 8(9): 1628-1630. https://www.cnki.com.cn/Article/CJFDTOTAL-SWCX200809015.htm
[43]	丁畅, 银萍, 赵奇, 等. 荷叶碱通过抑制PI3K/Akt/mTOR通路促进自噬减少巨噬细胞泡沫化的机制研究[J]. 中国病理生理杂志, 2020, 36(7): 1230-1236. doi: 10.3969/j.issn.1000-4718.2020.07.011
[44]	邹瑾, 赵真旺, 吴洁, 等. 荷叶碱对巨噬细胞源性泡沫细胞ABCA1表达与胆固醇流出的影响及机制[J]. 中国动脉硬化杂志, 2018, 26(9): 872-876, 924. doi: 10.3969/j.issn.1007-3949.2018.09.002
[45]	李娜, 宋金春. 荷叶碱对人肝癌细胞株HepG2凋亡及其作用机制[J]. 中国药物警戒, 2017, 14(12): 715-719, 726. doi: 10.3969/j.issn.1672-8629.2017.12.003
[46]	XU JX, YING AX, SHI TX. Nuciferine inhibits skin cutaneous melanoma cell growth by suppressing TLR4/NF-κB signaling[J]. Anti-Cancer Agents Med Chem, 2020, 20(17): 2099-2105. doi: 10.2174/1871520620666200811114607
[47]	LIU W, YI DD, GUO JL, et al. Nuciferine, extracted fromNelumbo nucifera Gaertn, inhibits tumor-promoting effect of nicotine involving Wnt/β-catenin signaling in non-small cell lung cancer[J]. J Ethnopharmacol, 2015, 165: 83-93. doi: 10.1016/j.jep.2015.02.015
[48]	ZHOU L, WANG QY, ZHANG H, et al. YAP inhibition by nuciferine via AMPK-mediated downregulation of HMGCR sensitizes pancreatic cancer cells to gemcitabine[J]. Biomolecules, 2019, 9(10): E620. http://www.ncbi.nlm.nih.gov/pubmed/31627466
[49]	LIU RM, XU P, CHEN Q, et al. A multiple-targets alkaloid nuciferine overcomes paclitaxel-induced drug resistancein vitro and in vivo[J]. Phytomedicine, 2020, 79: 153342. doi: 10.1016/j.phymed.2020.153342
[50]	蒲鹏, 张丽静, 雷森. 荷叶碱对胰岛素抵抗小鼠的干预研究[J]. 职业与健康, 2015, 31(10): 1317-1320. https://www.cnki.com.cn/Article/CJFDTOTAL-ZYJK201510010.htm
[51]	ZHANG C, DENG J, LIU D, et al. Nuciferine ameliorates hepatic steatosis in high-fat diet/streptozocin-induced diabetic mice through a PPARα/PPARγ coactivator-1α pathway[J]. Br J Pharmacol, 2018, 175(22): 4218-4228. doi: 10.1111/bph.14482
[52]	宋冠军. 荷叶碱等几种植物降糖功能成分对GLUT4的作用机制[D]. 武汉: 中南民族大学, 2018.
[53]	MA C, LI G, HE Y, et al. Pronuciferine and nuciferine inhibit lipogenesis in 3T3-L1 adipocytes by activating the AMPK signaling pathway[J]. Life Sci, 2015, 136: 120-125. doi: 10.1016/j.lfs.2015.07.001
[54]	NGUYEN KH, TA TN, PHAM TH, et al. Nuciferine stimulates insulin secretion from beta cells-an in vitro comparison with glibenclamide[J]. J Ethnopharmacol, 2012, 142(2): 488-495. doi: 10.1016/j.jep.2012.05.024
[55]	WANG MX, ZHAO XJ, CHEN TY, et al. Nuciferinealleviates renal injury by inhibiting inflammatory responses in fructose-fed rats[J]. J Agric Food Chem, 2016, 64(42): 7899-7910. doi: 10.1021/acs.jafc.6b03031
[56]	LI DY, LIU B, FAN YM, et al. Nuciferine protects against folic acid-induced acute kidney injury by inhibiting ferroptosis[J]. Br J Pharmacol, 2021, 178(5): 1182-1199. doi: 10.1111/bph.15364
[57]	KUMARIHAMY M, LEON F, PETTAWAY S, et al. In vitro opioid receptor affinity and in vivo behavioral studies of Nelumbo nucifera flower[J]. J Ethnopharmacol, 2015, 174: 57-65. doi: 10.1016/j.jep.2015.08.006
[58]	KETTENES-VAN DEN BOSCH JJ, SALEMINK CA, KHAN I. Biological activity of the alkaloids of Papaver bracteatum Lindl[J]. J Ethnopharmacol, 1981, 3(1): 21-38. doi: 10.1016/0378-8741(81)90012-X
[59]	CURTIS DR, LODGE D, BORNSTEIN JC. Nuciferine and central glutamate receptors[J]. J Pharm Pharmacol, 1979, 31(11): 795-797. http://europepmc.org/abstract/MED/41920
[60]	DAVIES J, POLC P. Effects of L-nuciferine on kainate, N-methyl-D-aspartate and acetylcholine excitation of cat spinal neurons[J]. J Pharm Pharmacol, 1979, 31(3): 178-179. http://europepmc.org/abstract/MED/34695
[61]	BHATTACHARYA SK, BOSE R, GHOSH P, et al. Psychopharmacological studies on (-)-nuciferine and its Hofmann degradation product atherosperminine[J]. Psychopharmacology, 1978, 59(1): 29-33. doi: 10.1007/BF00428026
[62]	HENG HL, CHEE CF, CHIN SP, et al. Synthesis and evaluation of nuciferine and roemerine enantiomers as 5-HT₂ and α₁ receptor antagonists[J]. Medchemcomm, 2018, 9(3): 576-582. doi: 10.1039/C7MD00629B
[63]	MCLENNAN H, WHEAL HV. The specificity of action of three possible antagonists of amino acid-induced neuronal excitations[J]. Neuropharmacology, 1976, 15(11): 709-712. doi: 10.1016/0028-3908(76)90041-1
[64]	郝如彬. 基于RhoA/ROCKⅡ信号通路探讨荷叶碱对脑缺血再灌注损伤保护的作用机制[D]. 长春: 长春中医药大学, 2020.
[65]	ZHANG LN, GAO JH, TANG P, et al. Nuciferine inhibits LPS-induced inflammatory response in BV₂ cells by activating PPAR-γ[J]. Int Immunopharmacol, 2018, 63: 9-13. doi: 10.1016/j.intimp.2018.07.015
[66]	CHEN X, ZHENG X, ZHANG M, et al. Nuciferine alleviates LPS-induced mastitis in mice via suppressing the TLR4-NF-κB signaling pathway[J]. Inflamm Res, 2018, 67(11/12): 903-911. http://www.onacademic.com/detail/journal_1000040411586810_bd73.html
[67]	WU HC, YANG YP, GUO S, et al. Nuciferine ameliorates inflammatory responses by inhibiting the TLR4-mediated pathway in lipopolysaccharide-induced acute lung injury[J]. Front Pharmacol, 2017, 8: 939. doi: 10.3389/fphar.2017.00939
[68]	ZHANG C, DENG JJ, LIU D, et al. Nuciferine inhibits proinflammatory cytokines via the PPARs in LPS-induced RAW264.7 cells[J]. Molecules, 2018, 23(10): 2723. doi: 10.3390/molecules23102723
[69]	LIU CM, KAO CL, WU HM, et al. Antioxidant and anticancer aporphine alkaloids from the leaves of Nelumbo nucifera Gaertn. cv. Rosa-plena[J]. Molecules, 2014, 19(11): 17829-17838. doi: 10.3390/molecules191117829
[70]	LIN RJ, WU MH, MA YH, et al. Anthelmintic activities of aporphine from Nelumbo nucifera gaertn. cv. Rosa-plena against Hymenolepis nana[J]. Int J Mol Sci, 2014, 15(3): 3624-3639. doi: 10.3390/ijms15033624
[71]	SHU GW, QIU YH, HAO J, et al. Nuciferine alleviates acute alcohol-induced liver injury in mice: Roles of suppressing hepatic oxidative stress and inflammation via modulating miR-144/Nrf2/HO-1 cascade[J]. J Funct Foods, 2019, 58: 105-113. doi: 10.1016/j.jff.2019.04.055
[72]	SONG C, CAO J, LEI Y, et al. Nuciferine prevents bone loss by disrupting multinucleated osteoclast formation and promoting type H vessel formation[J]. Faseb J, 2020, 34(3): 4798-4811. doi: 10.1096/fj.201902551R
[73]	CHAN JD, ACHARYA S, DAY TA, et al. Pharmacological profiling an abundantly expressed schistosome serotonergic GPCR identifies nuciferine as a potent antagonist[J]. Int J Parasitol Drugs Drug Resist, 2016, 6(3): 364-370. doi: 10.1016/j.ijpddr.2016.06.001
[74]	陈云宪, 唐良秋, 梁家荣, 等. 荷叶碱通过上调SDF-1/CXCR4信号通路促进人主动脉内皮细胞增殖[J]. 中国动脉硬化杂志, 2020, 28(11): 981-985. doi: 10.3969/j.issn.1007-3949.2020.11.011
[75]	HU L, XU W, ZHANG X, et al. In-vitro and in-vivo evaluations of cytochrome P450 1A2 interactions with nuciferine[J]. J Pharm Pharmacol, 2010, 62(5): 658-662. doi: 10.1211/jpp.62.05.0015
[76]	林森, 侯曙光, 金伶伶, 等. 荷叶碱对野生型和突变型囊性纤维化跨膜电导调节因子氯离子通道的激活作用[J]. 中国临床药理学与治疗学, 2008, 13(2): 138-143. doi: 10.3969/j.issn.1009-2501.2008.02.003
[77]	何晓曦. 荷叶生物碱的分析及其体内药代动力学研究[D]. 天津: 天津科技大学, 2012.
[78]	王玉霞, 刘斌, 石任兵, 等. RP-HPLC法测定Beagle犬血浆中荷叶碱的浓度及药动学研究[J]. 药物分析杂志, 2008, 28(9): 1418-1421. https://www.cnki.com.cn/Article/CJFDTOTAL-YWFX200809005.htm
[79]	刘海龙, 王江, 林岱宗, 等. 先导化合物结构优化策略(二): 结构修饰降低潜在毒性[J]. 药学学报, 2014, 49(1): 1-15. doi: 10.3969/j.issn.1008-7303.2014.01.01