Leonurine

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Leonurine
Leonurine structure.png
Names
IUPAC name
4-(Diaminomethylideneamino)butyl 4-hydroxy-3,5-dimethoxybenzoate
Identifiers
3D model (JSmol)
ChemSpider
ECHA InfoCard 100.208.686 Edit this at Wikidata
KEGG
UNII
  • InChI=1S/C14H21N3O5/c1-20-10-7-9(8-11(21-2)12(10)18)13(19)22-6-4-3-5-17-14(15)16/h7-8,18H,3-6H2,1-2H3,(H4,15,16,17) checkY
    Key: WNGSUWLDMZFYNZ-UHFFFAOYSA-N checkY
  • InChI=1/C14H21N3O5/c1-20-10-7-9(8-11(21-2)12(10)18)13(19)22-6-4-3-5-17-14(15)16/h7-8,18H,3-6H2,1-2H3,(H4,15,16,17)
    Key: WNGSUWLDMZFYNZ-UHFFFAOYAI
  • O=C(OCCCC/N=C(\N)N)c1cc(OC)c(O)c(OC)c1
Properties
C14H21N3O5
Molar mass 311.338 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

Leonurine (also known as "SCM-198" in research) is a pseudoalkaloid that has been isolated from Leonotis leonurus, Leonotis nepetifolia, Leonotis artemisia, Leonurus cardiaca (Motherwort), Leonurus sibiricus, as well as other plants of family Lamiaceae.[citation needed] Leonurine is easily extracted into water.[1]

Pharmacology[edit]

Leonurine weakly binds to multiple GABA receptor sites including the GABA-A receptor.[2][3] but shows much higher affinity as an 5-HT3A antagonist[4] 5-HT3A antagonists have been shown to help prevent nausea and vomiting as well as the negative effects of serotonin in the G.I tract.[5][6]

Leonurine can regulate a variety of functions including oxidative stress, inflammation, fibrosis, apoptosis, and metabolic disorder.[7][8][9]

Leonurine has demonstrated antidepressant-like action and has been shown to increase levels of 5-hydroxytryptamine, noradrenaline, and dopamine in chronic mild stress studies on mice and inhibits the production of proinflammatory cytokines.[10][11][12]

Leonurine has been investigated as a potential treatment for cardiovascular disorders.[13][14][15][16] and protects against oxidative damage from ischemic stroke and demonstrates neuroprotective activity against focal cerebral ischemia brain injury induced on rats.[17][18][19]

Leonurine protects mice from pneumonia induced by influenza A[20]

Leonurine has demonstrated anti-cancer activity in vitro and in vivio.[21][22][23][24][25]

Metabolites[edit]

Metabolites of Leonurine in Rats dosed orally include Leonurine-10-O-sulfate (The sulfate conjugate of Leonurine), Leonurine-10-O-β-D-glucuronide (The glucuronide metabolite of Leonurine) and a O-demethylated Leonurine analog that has not yet had its structure definitively confirmed.[26]

Chemical synthesis[edit]

Leonurine can be synthesized starting from eudesmic acid. Reaction with sulfuric acid produces syringic acid. Protection with ethyl chloroformate followed by reaction with thionyl chloride SOCl2 and then tetrahydrofuran yields 4-carboethoxysyringic acid 4-chloro-1-butyl ester. The chloride is then converted to an amino group via a Gabriel synthesis (with potassium pthalimide) followed by hydrazinolysis (Ing–Manske procedure). The final step is reaction of the amine with S-methylisothiourea hemisulfate salt.

Leonurine synthesis[1]

See also[edit]

References[edit]

  1. ^ a b "The Leonurine and its preparation". An Hui New Star Pharmaceutical Development Co. 2008. Archived from the original on 2008-05-15. Retrieved 2008-08-28.
  2. ^ Çiçek, S. S. (2018). "Structure-Dependent Activity of Natural GABA(A) Receptor Modulators". Molecules (Basel, Switzerland). 23 (7): 1512. doi:10.3390/molecules23071512. PMC 6100244. PMID 29932138.
  3. ^ Rauwald, H. W.; Kuchta, K.; Savtschenko, A.; Brückner, A.; Rusch, C.; Appel, K. (August 2013). "GABAA receptor binding assays of standardized Leonurus cardiaca and L. japonicus extracts as well as their isolated constituents". Planta Medica. 79 (13): PN52. doi:10.1055/s-0033-1352395.
  4. ^ Hoffmann, Katrin M.; Herbrechter, Robin; Ziemba, Paul M.; Lepke, Peter; Beltrán, Leopoldo; Hatt, Hanns; Werner, Markus; Gisselmann, Günter (2016). "Kampo Medicine: Evaluation of the Pharmacological Activity of 121 Herbal Drugs on GABAA and 5-HT3A Receptors". Frontiers in Pharmacology. 7: 219. doi:10.3389/fphar.2016.00219. PMC 4965468. PMID 27524967.
  5. ^ Theriot, Jonathan; Wermuth, Harrison R.; Ashurst, John V. (2022). "Antiemetic Serotonin-5-HT3 Receptor Blockers". StatPearls. StatPearls Publishing. PMID 30020690.
  6. ^ "List of 5HT3 receptor antagonists (5hydroxytryptamine receptor antagonists)".
  7. ^ Li, Yun-yun; Lin, Yi-kong; Liu, Xin-hua; Wang, Li; Yu, Min; Li, Da-jin; Zhu, Yi-zhun; Du, Mei-rong (February 2020). "Leonurine: From Gynecologic Medicine to Pleiotropic Agent". Chinese Journal of Integrative Medicine. 26 (2): 152–160. doi:10.1007/s11655-019-3453-0. PMID 31069695. S2CID 148571306.
  8. ^ Li, Nan; Xu, Qiang; Liu, Qingping; Pan, Dongmei; Jiang, Yubao; Liu, Minying; Liu, Mingling; Xu, Hanshi; Lin, Changsong (1 August 2017). "Leonurine attenuates fibroblast-like synoviocyte-mediated synovial inflammation and joint destruction in rheumatoid arthritis". Rheumatology. 56 (8): 1417–1427. doi:10.1093/rheumatology/kex142. PMID 28431044.
  9. ^ Zheng, Suna; Zhuang, Tianchi; Tang, Yajun; Wu, Ruihan; Xu, Ting; Leng, Tian; Wang, Yao; Lin, Zheng; Ji, Minghui (23 August 2021). "Leonurine protects against ulcerative colitis by alleviating inflammation and modulating intestinal microflora in mouse models". Experimental and Therapeutic Medicine. 22 (5): 1199. doi:10.3892/etm.2021.10633. PMC 8422400. PMID 34584544.
  10. ^ Jia, Miaomiao; Li, Chenxin; Zheng, Ying; Ding, Xiaojing; Chen, Meng; Ding, Jianhua; Du, Renhong; Lu, Ming; Hu, Gang (1 November 2017). "Leonurine Exerts Antidepressant-Like Effects in the Chronic Mild Stress-Induced Depression Model in Mice by Inhibiting Neuroinflammation". International Journal of Neuropsychopharmacology. 20 (11): 886–895. doi:10.1093/ijnp/pyx062. PMC 5737563. PMID 29016795.
  11. ^ Shi, Xue Ru; Hong, Zhen Yi; Liu, Hong Rui; Zhang, Yu Chen; Zhu, Yi Zhun (1 July 2011). "Neuroprotective effects of SCM198 on 6-hydroxydopamine-induced behavioral deficit in rats and cytotoxicity in neuronal SH-SY5Y cells". Neurochemistry International. 58 (8): 851–860. doi:10.1016/j.neuint.2010.11.007. PMID 21093517. S2CID 33986318.
  12. ^ Liao, Li; Zhou, Mengting; Wang, Jing; Xue, Xinyan; Deng, Ying; Zhao, Xingtao; Peng, Cheng; Li, Yunxia (4 November 2021). "Identification of the Antithrombotic Mechanism of Leonurine in Adrenalin Hydrochloride-Induced Thrombosis in Zebrafish via Regulating Oxidative Stress and Coagulation Cascade". Frontiers in Pharmacology. 12: 742954. doi:10.3389/fphar.2021.742954. PMC 8600049. PMID 34803688.
  13. ^ Huang, Lu; Xu, Ding‐Qiao; Chen, Yan‐Yan; Yue, Shi‐Jun; Tang, Yu‐Ping (2021). "Leonurine, a potential drug for the treatment of cardiovascular system and central nervous system diseases". Brain and Behavior. 11 (2): e01995. doi:10.1002/brb3.1995. PMC 7882174. PMID 33300684.
  14. ^ Wang, Ruiyu; Peng, Linqian; Lv, Dingyi; Shang, Feifei; Yan, Jianghong; Li, Guoxing; Li, Dan; Ouyang, Jing; Yang, Jiadan (February 2021). "Leonurine Attenuates Myocardial Fibrosis Through Upregulation of miR-29a-3p in Mice Post-myocardial Infarction". Journal of Cardiovascular Pharmacology. 77 (2): 189–199. doi:10.1097/FJC.0000000000000957. PMID 33235025. S2CID 227168673.
  15. ^ Zhu, Qing; Cai, Weimin; Sha, Xianyi; Ma, Guo; Zheng, Yuanting; Shi, Xueru; Zhu, Yizhun (April 2012). "Quantification of leonurine, a novel potential cardiovascular agent, in rat plasma by liquid chromatography-tandem mass spectrometry and its application to pharmacokinetic study in rats: LC-MS/MS method for determination of leonurine and its application". Biomedical Chromatography. 26 (4): 518–523. doi:10.1002/bmc.1699. PMID 21882210.
  16. ^ Liu, Xin-Hua; Pan, Li-Long; Deng, Hai-Yan; Xiong, Qing-Hui; Wu, Dan; Huang, Guo-Ying; Gong, Qi-Hai; Zhu, Yi-Zhun (January 2013). "Leonurine (SCM-198) attenuates myocardial fibrotic response via inhibition of NADPH oxidase 4". Free Radical Biology and Medicine. 54: 93–104. doi:10.1016/j.freeradbiomed.2012.10.555. PMID 23127783.
  17. ^ Xie, Yan‐Zhao; Zhang, Xiang‐Jian; Zhang, Cong; Yang, Yang; He, Jun‐Na; Chen, Yan‐Xia (2019). "Protective effects of leonurine against ischemic stroke in mice by activating nuclear factor erythroid 2‐related factor 2 pathway". CNS Neuroscience & Therapeutics. 25 (9): 1006–1017. doi:10.1111/cns.13146. PMC 6698971. PMID 31087454.
  18. ^ Li, Feng; Zhu, Sifeng; Jiang, Qihui; Hou, Chenhui; Pang, Tao; Zhang, Liang; Li, Wenbao (7 July 2021). "Novel Stachydrine–Leonurine Conjugate SL06 as a Potent Neuroprotective Agent for Cerebral Ischemic Stroke". ACS Chemical Neuroscience. 12 (13): 2478–2490. doi:10.1021/acschemneuro.1c00200. PMID 34180238. S2CID 235660771.
  19. ^ Liu, Haichao; Zhang, Xiangjian; Du, Yuanyuan; Ji, Hui; Li, Shuya; Li, Litao; Xing, Yinxue; Zhang, Xiaolin; Dong, Lipeng; Wang, Chaohui; Zhao, Kang; Ji, Ye; Cao, Xiaoyun (September 2012). "Leonurine protects brain injury by increased activities of UCP4, SOD, CAT and Bcl-2, decreased levels of MDA and Bax, and ameliorated ultrastructure of mitochondria in experimental stroke". Brain Research. 1474: 73–81. doi:10.1016/j.brainres.2012.07.028. PMID 22842526. S2CID 24119195.
  20. ^ Qiu, Li-Nan; Tan, Ya-Rong; Luo, Yu-Ju; Chen, Xiao-Juan (23 September 2021). "Leonurine protects against influenza A virus infection-induced pneumonia in mice". Pathogens and Disease. 79 (7): ftab045. doi:10.1093/femspd/ftab045. PMID 34543397.
  21. ^ Zhuang, Qiang; Ruan, Lina; Jin, Ting; Zheng, Xiangkuo; Jin, Zhenlin (2021). "Anti-leukaemia effects of leonurine in vitro and in vivo". General Physiology and Biophysics. 40 (5): 397–407. doi:10.4149/gpb_2021018. PMID 34602453.
  22. ^ Liu, Hui-Min; Guo, Chun-Ling; Zhang, Yao-Fang; Chen, Jian-Fang; Liang, Zhi-Peng; Yang, Lin-Hua; Ma, Yan-Ping (2021). "Leonurine-Repressed miR-18a-5p/SOCS5/JAK2/STAT3 Axis Activity Disrupts CML malignancy". Frontiers in Pharmacology. 12: 657724. doi:10.3389/fphar.2021.657724. PMC 8087248. PMID 33935775.
  23. ^ Mao, Feng; Zhang, Liang; Cai, Ming-Hui; Guo, Hong; Yuan, Hai-Hua (2 November 2015). "Leonurine hydrochloride induces apoptosis of H292 lung cancer cell by a mitochondria-dependent pathway". Pharmaceutical Biology. 53 (11): 1684–1690. doi:10.3109/13880209.2014.1001406. PMID 25856714. S2CID 207526411.
  24. ^ Lin, Min; Pan, Chunyu; Xu, Wenbin; Li, Jingwei; Zhu, Xueqiong (15 May 2020). "Leonurine Promotes Cisplatin Sensitivity in Human Cervical Cancer Cells Through Increasing Apoptosis and Inhibiting Drug-Resistant Proteins". Drug Design, Development and Therapy. 14: 1885–1895. doi:10.2147/DDDT.S252112. PMC 7237110. PMID 32523334.
  25. ^ Li, Xiaocui; Xie, Yushan; Qu, Wei; Ou, Xiaojun; Ou, Xiaowen; Wang, Chuang; Qi, Xiaoxiao; Wang, Ying; Liu, Zhongqiu; Zhu, Lijun (November 2020). "Breast Cancer Resistance Protein and Multidrug Resistance Protein 2 Mediate the Disposition of Leonurine-10-O-β-glucuronide". Current Drug Metabolism. 21 (13): 1060–1067. doi:10.2174/1389200221999201116142742. PMID 33198612. S2CID 226985047.
  26. ^ Zhu, Qing; Zhang, Jinlian; Yang, Ping; Tan, Bo; Liu, Xinhua; Zheng, Yuanting; Cai, Weimin; Zhu, Yizhun (2014). "Characterization of Metabolites of Leonurine (SCM-198) in Rats after Oral Administration by Liquid Chromatography/Tandem Mass Spectrometry and NMR Spectrometry". The Scientific World Journal. 2014: 947946. doi:10.1155/2014/947946. PMC 3956552. PMID 24772041.

Further reading[edit]

  • Cheng KF, Yip CS, Yeung HW, Kong YC (May 1979). "Leonurine, an improved synthesis". Experientia. 35 (5): 571–2. doi:10.1007/BF01960323. PMID 446644. S2CID 22601565.
  • Huang, L., Xu, D. Q., Chen, Y. Y., Yue, S. J., & Tang, Y. P. (2021). Leonurine, a potential drug for the treatment of cardiovascular system and central nervous system diseases. Brain and behavior, 11(2), e01995. PMID 33300684 PMC 7882174 doi:10.1002/brb3.1995
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