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Palmatine

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Palmatine is a protoberberine alkaloid found in several plants including Coptis chinensis[1] (Rhizoma coptidis, chinese goldthread), Corydalis yanhusuo,[2]Tinospora cordifolia[3] (gurjo, heart-leaved moonseed), Tinospora sagittata,[4]Phellodendron amurense[5] (amur cork tree), and Stephania yunnanensis.[6]

It is the major component of the protoberberine extract from Enantia chlorantha.[7]

It has been studied for its potential use in the treatment of jaundice, dysentery, hypertension, inflammation, and liver-related diseases.[8] This compound also has weak in vitro activity against flavivirus.[9]

Biosynthesis

The biosynthesis of palmatine starts with tyrosine and proceeds via (S)-reticuline in a pathway leading to benzylisoquinoline alkaloids.[10][11] The final step is catalysed by the enzyme tetrahydroberberine oxidase, which oxidises tetrahydropalmatine:[12][13]

Representación en 2D de la estructura química de la tetrahidropalmatina.
tetrahydropalmatine
+ H+
 
 
2 O2
2 H2O2
Flecha de reacción hacia la derecha con sustrato(s) menor(es) desde la parte superior izquierda y producto(s) menor(es) hacia la parte superior derecha.
 
 
 
Representación bidimensional de la estructura química de la palmatina.
palmatine

Alternatively, a methylation reaction catalysed by columbamine O-methyltransferase produces palmatine from columbamine. The methyl group comes from the cofactor, S-adenosyl methionine (SAM). This enzyme was characterised from Berberis wilsoniae.[14]

Representación en 2D de la estructura química de la columbamina.
columbamine
+ SAM
 
 
 
 
Flecha de reacción hacia la derecha
 
 
 
Representación bidimensional de la estructura química de la palmatina.
palmatine
+ SAH
 

Metabolism

In Corydalis cava, palmatine is converted to corydaline by the enzyme corydaline synthase. The methyl group comes from SAM and the reaction also requires nicotinamide adenine dinucleotide phosphate (NADPH).[15]

Representación bidimensional de la estructura química de la palmatina.
palmatine
+ SAM+ 2 NADPH
 
 
H+
 
Flecha de reacción hacia la derecha con sustrato(s) menor(es) desde la parte superior izquierda.
 
 
 
Representación en 2D de la estructura química de la coridalina.
corydaline
+ SAH+ 2 NADP+
 

Pharmacology

Neuroprotective activity

Palmatine is an inhibitor of acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and neuraminidase-1 (NA-1), and has potential applications in the therapy of Alzheimer's disease. It was found that the positively charged nitrogen on palmatine binds in the gorge of active sire of AChE.[16]

Research show that palmatine had antidepressant effect. It was achieved by regulating brain catalase levels, monoamine oxidase-A (MAO-A) activity, lipid peroxidation, plasma nitrite and corticosterone levels.[17]

Regulating blood lipid activity

Palmatine achieved hypoglycemic effects by inducing insulin release and insulin-mimicking activity.[18][19] In addition, studies found that palmatine also inhibited the activity of lens aldose reductase,[20] sucrase and maltase.[21] In vivo research showed that palmatine reduced serum total cholesterol (TC) and triglycerides (TG) and increased serum high-density lipoprotein cholesterol.[22]

Anticancer activity

Research showed that palmatine had broad anti-cancer activity. Palmatine had significant growth inhibitory effects on seven human cancer cell lines: 7701QGY, SMMC7721, HepG2, CEM, CEM/VCR, K III and Lewis.[23] In addition, palmatine also had anti-cancer activity on MCF-7, U251, KB,[24] CHOK-1, HT-29 and SiHacell lines.[25] Palmatine induced apoptosis in human skin epithelial carcinoma cells (A431) in a concentration- and time-dependent manner via damaging severely to DNA and inhibiting the activity of Bcl-2 protein.[26][27][28] In addition, palmatine can inhibit the proliferation and infiltration of cancer cells.

Antibacterial and antiviral activity

Palmitine has inhibitory effect on Gram-positive bacteria which is significantly stronger than that on Gram-negative bacteria,[29] and 9-O-substituted palmatine derivatives exhibited stronger antibacterial activity.[30][31]

Anti-inflammatory activity

Studies have shown that palmatine can decrease the production of pro-inflammatory factors and increase the production of anti-inflammatory factors.[32]

Other pharmacological activity

Studies have shown that palmatine chave antioxidant activity,[33][34] had a protective effect on gastric ulcer,[35] derivatives of palmatine were more effective against ulcerative colitis, including low cytotoxicity to intestinal epithelial cells.[36] In addition, palmatine might have the antiarrhythmic effect,[37] and provideprotection from myocardial ischemia-reperfusion injury.[38]

Toxicity

A large number of studies have shown that palmatine has a complex effect on the metabolism of enzymes in the liver, and that palmatine has significant DNA toxicity.[39] However, some 9-O-substituted palmatine derivatives exhibited less toxic than palmatine.[40] In addition, palmatine had higher affinity to nucleic acids than serum proteins, which make them suitable candidates for delivery by serum proteins.[41]

See also

References

  1. ↑Yang, Seong Baek; Kim, Eun Hee; Kim, Seung Hee; Kim, Young Hun; Oh, Weontae; Lee, Jin-Tae; Jang, Young-Ah; Sabina, Yeasmin; Ji, Byung Chul; Yeum, Jeong Hyun (2018-09-17). "Electrospinning Fabrication of Poly(vinyl alcohol)/Coptis chinensis Extract Nanofibers for Antimicrobial Exploits". Nanomaterials. 8 (9): 734. doi:10.3390/nano8090734. ISSN 2079-4991. PMC 6164458. PMID 30227671.
  2. ↑Zhang, Qian; Chen, Cen; Wang, Feng-Qin; Li, Chun-Hong; Zhang, Qi-Hui; Hu, Yuan-Jia; Xia, Zhi-Ning; Yang, Feng-Qing (2016-12-01). "Simultaneous screening and analysis of antiplatelet aggregation active alkaloids from Rhizoma Corydalis". Pharmaceutical Biology. 54 (12): 3113–3120. doi:10.1080/13880209.2016.1211714. ISSN 1388-0209. PMID 27558975.
  3. ↑Kumar, Peeyush; Srivastava, Vartika; Chaturvedi, Rakhi; Sundar, Durai; Bisaria, V. S. (2017-08-01). "Elicitor enhanced production of protoberberine alkaloids from in vitro cell suspension cultures of Tinospora cordifolia (Willd.) Miers ex Hook. F. & Thoms". Plant Cell, Tissue and Organ Culture. 130 (2): 417–426. doi:10.1007/s11240-017-1237-0. ISSN 1573-5044. S2CID 41951538.
  4. ↑Rong, Qian; Xu, Min; Dong, Qi; Zhang, Yuli; Li, Yinglun; Ye, Gang; Zhao, Ling (2016-08-30). "In vitro and in vivo bactericidal activity of Tinospora sagittata (Oliv.) Gagnep. var. craveniana (S.Y.Hu) Lo and its main effective component, palmatine, against porcine Helicobacter pylori". BMC Complementary and Alternative Medicine. 16 (1): 331. doi:10.1186/s12906-016-1310-y. ISSN 1472-6882. PMC 5006617. PMID 27576439.
  5. ↑Sun, Minglong; Xu, Lijiao; Peng, Yingli; Liu, Tong; Zhang, Yuhong; Zhou, Zhiqiang (2016-04-01). "Multiscale analysis of the contents of palmatine in the Nature populations of Phellodendron amurense in Northeast China". Journal of Forestry Research. 27 (2): 265–272. doi:10.1007/s11676-015-0200-3. ISSN 1993-0607. S2CID 15369649.
  6. ↑Xin, Aiyi; Zhang, Yaming; Zhang, Yanxia; Di, Duolong; Liu, Junxi (October 2018). "Development of an HPLC-DAD method for the determination of five alkaloids in Stephania yunnanensis Lo and in rat plasma after oral dose of Stephania yunnanensis Lo extracts". Biomedical Chromatography. 32 (10) e4292. doi:10.1002/bmc.4292. ISSN 1099-0801. PMID 29782649. S2CID 29167917.
  7. ↑Virtanen P., Njimi T., Ekotto Mengata D. (1989). "Clinical trials of hepatitis cure with protoberberine alkaloids of Enantia Chlorantha". Eur. J. Clin. Pharmacol. 36: A123.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ↑Bhadra K, Kumar GS (January 2010). "Therapeutic potential of nucleic acid-binding isoquinoline alkaloids: Binding aspects and implications for drug design". Medicinal Research Reviews. 31 (6): 821–862. doi:10.1002/med.20202. PMID 20077560. S2CID 206250975.
  9. ↑Jia, Fan; Zou, Gang; Fan, Jingjing; Yuan, Zhiming (2010). "Identification of palmatine as an inhibitor of West Nile virus". Archives of Virology. 155 (8): 1325–1329. doi:10.1007/s00705-010-0702-4. PMID 20496087.
  10. ↑Tian, Ya; Kong, Lingzhe; Li, Qi; Wang, Yifan; Wang, Yongmiao; An, Zhoujie; Ma, Yuwei; Tian, Lixia; Duan, Baozhong; Sun, Wei; Gao, Ranran; Chen, Shilin; Xu, Zhichao (2024). "Structural diversity, evolutionary origin, and metabolic engineering of plant specialized benzylisoquinoline alkaloids". Natural Product Reports. 41 (11): 1787–1810. doi:10.1039/d4np00029c. PMID 39360417.
  11. ↑Begley, Tadhg P. (2009). Encyclopedia of Chemical Biology. Vol. 10. Wiley. pp. 1569–1570. doi:10.1002/cbic.200900262. ISBN 978-0-471-75477-0.
  12. ↑Mascavage, Linda M.; Jasmin, Serge; Sonnet, Philip E.; Wilson, Michael; Dalton, David R. (2010). "Alkaloids". Ullmann's Encyclopedia of Industrial Chemistry. p. 54. doi:10.1002/14356007.a01_353.pub2. ISBN 978-3-527-30385-4.
  13. ↑Enzyme 1.3.3.8 at KEGG Pathway Database.
  14. ↑Rueffer M, Amann M, Zenk MH (1986). "S-Adenosyl-L-methionine:columbamine O-methyltransferase, a compartmentalized enzyme in protoberberine biosynthesis". Plant Cell Reports. 5 (3): 182–185. Bibcode:1986PCelR...5..182R. doi:10.1007/BF00269113. PMID 24248127.
  15. ↑Rueffer M, Bauer W, Zenk MH (1994). "The formation of corydaline and related alkaloids in Corydalis cava in vivo and in vitro". Can. J. Chem. 72 (1): 170–175. Bibcode:1994CaJCh..72..170R. doi:10.1139/v94-026.
  16. ↑Mukherjee, Pulok K.; Kumar, Venkatesan; Mal, Mainak; Houghton, Peter J. (2007-04-10). "Acetylcholinesterase inhibitors from plants". Phytomedicine. 14 (4): 289–300. doi:10.1016/j.phymed.2007.02.002. ISSN 0944-7113. PMID 17346955.
  17. ↑Dhingra, Dinesh; Bhankher, Arun (2014-02-01). "Behavioral and biochemical evidences for antidepressant-like activity of palmatine in mice subjected to chronic unpredictable mild stress". Pharmacological Reports. 66 (1): 1–9. doi:10.1016/j.pharep.2013.06.001. ISSN 1734-1140. PMID 24905299. S2CID 14391622.
  18. ↑Patel, Mayurkumar B.; Mishra, Shrihari (September 2011). "Hypoglycemic activity of alkaloidal fraction of Tinospora cordifolia". Phytomedicine. 18 (12): 1045–1052. doi:10.1016/j.phymed.2011.05.006. ISSN 0944-7113. PMID 21665451.
  19. ↑Ma, Bingxin; Tong, Jing; Zhou, Gao; Mo, Qigui; He, Jingsheng; Wang, Youwei (March 2016). "Coptis chinensis inflorescence ameliorates hyperglycaemia in 3T3-L1 preadipocyte and streptozotocin-induced diabetic mice". Journal of Functional Foods. 21: 455–462. doi:10.1016/j.jff.2015.12.021. ISSN 1756-4646.
  20. ↑Patel, Mayurkumar B.; Mishra, Shrihari (2012-02-01). "Isoquinoline Alkaloids from Tinospora cordifolia Inhibit Rat Lens Aldose Reductase". Phytotherapy Research. 26 (9): 1342–1347. doi:10.1002/ptr.3721. ISSN 0951-418X. PMID 22294283. S2CID 34663821.
  21. ↑ Patel, Mayurkumar B.; Mishra, Shrihari M. (enero de 2012). "La magnoflorina del tallo de Tinospora cordifolia inhibe la α-glucosidasa y es antiglucémica en ratas" . Journal of Functional Foods . 4 (1): 79– 86. doi : 10.1016/j.jff.2011.08.002 . ISSN 1756-4646 . 
  22. ↑ Mamá, cuelga; Hu, Yinran; Zou, Zongyao; Feng, Min; Sí, Xiaoli; Li, Xuegang (4 de abril de 2016). "Efecto antihiperglucemia y antihiperlipidemia de los alcaloides de protoberberina de Rhizoma Coptidis en células HepG2 y ratones diabéticos KK-Ay". Investigación sobre desarrollo de fármacos . 77 (4): 163– 170. doi : 10.1002/ddr.21302 . ISSN 0272-4391 . PMID 27045983 . S2CID 31823923 .   
  23. ↑ Zhang, Lei; Li, Jingjing; Ma, Fei; Yao, Shining; Li, Naisan; Wang, Jing; Wang, Yongbin; Wang, Xiuzhen; Yao, Qizheng (2012-09-25). "Síntesis y evaluación de la citotoxicidad de análogos de 13-n-alquil berberina y palmatina como agentes anticancerígenos" . Molecules . 17 ( 10): 11294– 11302. doi : 10.3390/molecules171011294 . ISSN 1420-3049 . PMC 6268624. PMID 23011273 .   
  24. ↑ Costa, Emmanoel Vilaça; Cruz, Pedro Ernesto O. da; Pinheiro, María Lucía B.; Marqués, Francisco A.; Ruiz, Ana Lucía TG; Marchetti, Gabriela M.; Carvalho, João Ernesto de; Barison, Andersson; Maia, Beatriz Helena LNS (2013). "Alcaloides de aporfina y tetrahidroprotoberberina de las hojas de Guatteria friesiana (Annonaceae) y sus actividades citotóxicas" . Revista de la Sociedad Química Brasileña . doi : 10.5935/0103-5053.20130103 . ISSN 0103-5053 . 
  25. ↑ Bala, Manju; Pratap, Kunal; Verma, Praveen Kumar; Singh, Bikram; Padwad, Yogendra (diciembre de 2015). "Validación del potencial etnomedicinal de Tinospora cordifolia para actividades anticancerígenas e inmunomoduladoras y cuantificación de moléculas bioactivas por HPTLC". Journal of Ethnopharmacology . 175 : 131–137 . doi : 10.1016/j.jep.2015.08.001 . ISSN 0378-8741 . PMID 26253577 .  
  26. ↑ Ali, Daoud; Ali, Huma (2014-07-03). "Evaluación del daño al ADN y la citotoxicidad de la palmatina en células de carcinoma epitelial de piel humana". Toxicological & Environmental Chemistry . 96 (6): 941– 950. Bibcode : 2014TxEC...96..941A . doi : 10.1080/02772248.2014.987510 . ISSN 0277-2248 . S2CID 84213943 .  
  27. ↑ Wu, Juan; Xiao, Qicai; Zhang, Na; Xue, Changhu; Leung, Albert Wingnang; Zhang, Hongwei; Tang, Qing-Juan; Xu, Chuanshan (septiembre de 2016). "Inactivación fotodinámica de células de cáncer de mama MCF-7 mediada por hidrocloruro de palmatina: eficacia y mecanismo de acción". Photodiagnosis and Photodynamic Therapy . 15 : 133–138 . doi : 10.1016/j.pdpdt.2016.07.006 . ISSN 1572-1000 . PMID 27444887 .  
  28. ^ Él, Qiyuan; Zhang, Hua (2020). "Hacia la matriz de heteroestructura vdW escalable" . Acta Physico-Chimica Sinica : 2003075– 0. doi : 10.3866/pku.whxb202003075 . ISSN 1000-6818 . 
  29. ↑ Deng, Yecheng; Zhang, Ming; Luo, Haiyu (mayo de 2012). "Identificación y actividad antimicrobiana de dos alcaloides de la planta medicinal tradicional china Tinospora capillipes". Industrial Crops and Products . 37 (1): 298– 302. doi : 10.1016/j.indcrop.2011.12.006 . ISSN 0926-6690 . 
  30. ↑ Li, ZC; Kong, XB; Mai, WP; Sun, GC; Zhao, SZ (2015). "Síntesis y actividad antimicrobiana de derivados de palmatina 9-o-sustituidos" . Indian Journal of Pharmaceutical Sciences . 77 (2): 196– 201. doi : 10.4103/0250-474x.156588 . ISSN 0250-474X . PMC 4442469. PMID 26009653 .   
  31. ↑ Song, Li; Zhang, Hai-Jing; Deng, An-Jun; Li, Jia; Li, Xiang; Li, Zhi-Hong; Zhang, Zhi-Hui; Wu, Lian-Qiu; Wang, Sheng-Qi; Qin, Hai-Lin (mayo de 2018). "Síntesis y relaciones estructura-actividad sobre las propiedades antibacterianas y anti-colitis ulcerosa de palmatinas cuaternarias 13-sustituidas y dihidropalmatinas 8-oxo-13-sustituidas". Bioorganic & Medicinal Chemistry . 26 (9): 2586– 2598. doi : 10.1016/j.bmc.2018.04.025 . ISSN 0968-0896 . PMID 29680749 .  
  32. ^ Yan, Baoqi; Wang, Dongsheng; Dong, Shuwei; Cheng, Zhangrui; Na, Lidong; Sang, Mengqi; Yang, Hongzao; Yang, Zhiqiang; Zhang, Shidong; Yan, Zuoting (abril de 2017). "La palmatina inhibe la vía NF-κB dependiente de TRIF contra la inflamación inducida por LPS en células epiteliales endometriales de cabra". Inmunofarmacología Internacional . 45 : 194–200 . doi : 10.1016/j.intimp.2017.02.004 . ISSN 1567-5769 . PMID 28236763 . S2CID 29087348 .   
  33. ↑ Ma, Bingxin; Zhu, Ling; Zang, Xiaoyan; Chen, Yuxin; Li, Dong; Wang, Youwei (octubre de 2013). "La inflorescencia de Coptis chinensis y sus principales alcaloides protegen contra el daño oxidativo inducido por la radiación ultravioleta B". Journal of Functional Foods . 5 (4): 1665– 1672. doi : 10.1016/j.jff.2013.07.010 . ISSN 1756-4646 . 
  34. ↑ Shia, Chi-Sheng; Hou, Yu-Chi; Juang, Shin-Hun; Tsai, Shang-Yuan; Hsieh, Pei-Hsun; Ho, Lu-Ching; Chao, Pei-Dawn Lee (2011). "Metabolismo y farmacocinética de San-Huang-Xie-Xin-Tang, una fórmula de medicina china rica en polifenoles, en ratas y actividad antioxidante ex vivo" . Medicina complementaria y alternativa basada en la evidencia . 2011 : 721293. doi : 10.1093/ecam/nep124 . ISSN 1741-427X . PMC 3137274. PMID 19737807 .   
  35. ↑Wang, Wei-Min; Nwabueze, OkechukwuPatrick; Yang, Hui; Zhai, Hong-Bin (2018). "High-performance liquid chromatography identification of gastroprotective and antioxidant effects of purified fractions A-E from the stem of Coscinium fenestratum". Pharmacognosy Magazine. 14 (55): 78. doi:10.4103/pm.pm_267_17. ISSN 0973-1296. S2CID 103671390.
  36. ↑Song, Li; Zhang, Hai-Jing; Deng, An-Jun; Li, Jia; Li, Xiang; Li, Zhi-Hong; Zhang, Zhi-Hui; Wu, Lian-Qiu; Wang, Sheng-Qi; Qin, Hai-Lin (May 2018). "Syntheses and structure-activity relationships on antibacterial and anti-ulcerative colitis properties of quaternary 13-substituted palmatines and 8-oxo-13-substituted dihydropalmatines". Bioorganic & Medicinal Chemistry. 26 (9): 2586–2598. doi:10.1016/j.bmc.2018.04.025. ISSN 0968-0896. PMID 29680749.
  37. ↑Guo, Rui; Zhang, Xiaoxiao; Su, Jin; Xu, Haiyu; Zhang, Yanqiong; Zhang, Fangbo; Li, Defeng; Zhang, Yi; Xiao, Xuefeng; Ma, Shuangcheng; Yang, Hongjun (May 2018). "Identifying potential quality markers of Xin-Su-Ning capsules acting on arrhythmia by integrating UHPLC-LTQ-Orbitrap, ADME prediction and network target analysis". Phytomedicine. 44: 117–128. doi:10.1016/j.phymed.2018.01.019. ISSN 0944-7113. PMID 29526583.
  38. ↑Tan, Hui-Li; Chan, Kok-Gan; Pusparajah, Priyia; Duangjai, Acharaporn; Saokaew, Surasak; Mehmood Khan, Tahir; Lee, Learn-Han; Goh, Bey-Hing (2016-10-07). "Rhizoma Coptidis: A Potential Cardiovascular Protective Agent". Frontiers in Pharmacology. 7: 362. doi:10.3389/fphar.2016.00362. ISSN 1663-9812. PMC 5054023. PMID 27774066.
  39. ↑Ali, Daoud; Ali, Huma (2014-07-03). "Assessment of DNA damage and cytotoxicity of palmatine on human skin epithelial carcinoma cells". Toxicological & Environmental Chemistry. 96 (6): 941–950. Bibcode:2014TxEC...96..941A. doi:10.1080/02772248.2014.987510. ISSN 0277-2248. S2CID 84213943.
  40. ↑ Li, ZC; Kong, XB; Mai, WP; Sun, GC; Zhao, SZ (2015). "Síntesis y actividad antimicrobiana de derivados de palmatina 9-o-sustituidos" . Indian Journal of Pharmaceutical Sciences . 77 (2): 196– 201. doi : 10.4103/0250-474x.156588 . ISSN 0250-474X . PMC 4442469. PMID 26009653 .   
  41. ↑ Khan, Asma Yasmeen; Suresh Kumar, Gopinatha (2015-12-01). "Alcaloides isoquinolínicos naturales: aspectos de unión a proteínas funcionales, albúminas séricas, hemoglobina y lisozima" . Biophysical Reviews . 7 (4): 407– 420. doi : 10.1007/s12551-015-0183-5 . ISSN 1867-2469 . PMC 5418488. PMID 28510102 .