Chelerythrine

Chelerythrine is a benzophenanthridine alkaloid present in the plant Chelidonium majus (greater celandine). It is a potent, selective, and cell-permeable protein kinase C inhibitor in vitro.[1] And an efficacious antagonist of G-protein-coupled CB1 receptors.[2] This molecule also exhibits anticancer qualities and it has served as a base for many potential novel drugs against cancer. Structurally, this molecule has two distinct conformations, one being a positively charged iminium form, and the other being an uncharged form, a pseudo-base.[3]

Chelerythrine
Names
IUPAC name
1,2-Dimethoxy-12-methyl[1,3]benzodioxolo[5,6-c]phenanthridin-12-ium
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.047.194
UNII
Properties
C21H18NO4
Molar mass 348.378 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

It is also found in the plants Zanthoxylum clava-herculis and Zanthoxylum rhoifolium, exhibiting antibacterial activity against Staphylococcus aureus and other human pathogens.[4][5]

Medical Relevance

Previous studies have showcased chelerythrine's ability to inhibit, or delay, cell proliferation, allowing it to be used to combat cancerous cells and promote cellular apoptosis, both in vivo and in vitro.[6][7] However, further studies of this alkaloid have revealed that it has low selectivity and it can also promote cellular apoptosis of non-cancerous cells, thus displaying cytotoxic behavior.[8][9][10] The creation of chelerythrine analogs have helped exploit this molecule's anticancer capabilities, while lessening its cytotoxic effects on non-cancerous cells. These novel analogs have been modified to have increased specificity for cancerous cells, thus decreasing cytotoxic effects and non-cancerous cell apoptosis.[11]

Cellular Apoptosis

Studies have shown that chelerythrine inhibits SERCA activity, more importantly the concentration needed to inhibit this enzyme is within range to that needed to inhibit protein kinase C. The negative regulation of SERCA activity results in accumulation of calcium ions in the cytoplasm, leading to the forced influx of calcium ions to the mitochondria. High calcium ion concentration in the mitochondria greatly alters its normal activity and leads to apoptosis signaling, and eventually cellular destruction. Other cellular transporters, like the PMCA, have also been shown to be negatively regulated by chelerythrine, preventing PMCA to effectively take out calcium ions from inside the cell. This further contributes to the loss of calcium ion balance within the cell and eventual cell death.[12][13]

Antibacterial Properties

Chelerythrine is a potent antibacterial agent that has aided in dealing with the emergence of antibacterial resistant bacteria. This molecule has the ability to disrupt a bacteria's cell wall and cell membrane, as well as preventing bacterial growth, all of which contribute to bacterial death.[14]

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References
  1. Chelerythrine from Fermentek
  2. Dhopeshwarkar, Amey S.; Jain, Saurabh; Liao, Chengyong; Ghose, Sudip K.; Bisset, Kathleen M.; Nicholson, Russell A. (2011-03-01). "The actions of benzophenanthridine alkaloids, piperonyl butoxide and (S)-methoprene at the G-protein coupled cannabinoid CB₁ receptor in vitro". European Journal of Pharmacology. 654 (1): 26–32. doi:10.1016/j.ejphar.2010.11.033. ISSN 1879-0712. PMID 21172340.
  3. Dostál, Jiří; Táborská, Eva; Slavík, Jiří; Potáček, Milan; de Hoffmann, Edmond (May 1995). "Structure of Chelerythrine Base". Journal of Natural Products. 58 (5): 723–729. doi:10.1021/np50119a010. ISSN 0163-3864.
  4. Gibbons, Simon; Leimkugel, Julia; Oluwatuyi, Moyo; et al. (2003). "<Activity of Zanthoxylum clava‐herculis extracts against multi‐drug resistant methicillin‐resistant Staphylococcus aureus (mdr‐MRSA)>". Phytotherapy Research. 17 (3): 274–275. doi:10.1002/ptr.1112. PMID 12672160.
  5. Tavares, Luciana de C; Zanon, Graciane; Weber, Andréia D.; et al. (2014). "<Structure-activity relationship of benzophenanthridine alkaloids from Zanthoxylum rhoifolium having antimicrobial activity>". PLOS ONE. 9 (5): e97000. Bibcode:2014PLoSO...997000T. doi:10.1371/journal.pone.0097000. PMC 4019524. PMID 24824737.
  6. Chen, Xiao-Meng; Zhang, Meng; Fan, Peng-Li; Qin, Yu-Hua; Zhao, Hong-Wei (June 2016). "Chelerythrine chloride induces apoptosis in renal cancer HEK-293 and SW-839 cell lines". Oncology Letters. 11 (6): 3917–3924. doi:10.3892/ol.2016.4520. ISSN 1792-1074. PMC 4888265. PMID 27313717.
  7. Kumar, Sanjay; Tomar, Munendra Singh; Acharya, Arbind (October 2015). "Chelerythrine delayed tumor growth and increased survival duration of Dalton's lymphoma bearing BALB/c H(2d) mice by activation of NK cells in vivo". Journal of Cancer Research and Therapeutics. 11 (4): 904–910. doi:10.4103/0973-1482.143342. ISSN 1998-4138. PMID 26881539.
  8. Vieira, Saulo Martins; de Oliveira, Vanessa Honorato; Valente, Raphael do Carmo; Moreira, Otacílio da Cruz; Fontes, Carlos Frederico Leite; Mignaco, Julio Alberto (2015-03-15). "Chelerythrine inhibits the sarco/endoplasmic reticulum Ca(2+)-ATPase and results in cell Ca(2+) imbalance". Archives of Biochemistry and Biophysics. 570: 58–65. doi:10.1016/j.abb.2015.02.019. ISSN 1096-0384. PMID 25721495.
  9. Shen, Yizhong; Zhu, Chunlei; Wang, Yaping; Xu, Jingjing; Xue, Ruyu; Ji, Fuyun; Wu, Yiwei; Wu, Zeyu; Zhang, Wencheng; Zheng, Zhi; Ye, Yingwang (2020-01-01). "Evaluation the binding of chelerythrine, a potentially harmful toxin, with bovine serum albumin". Food and Chemical Toxicology. 135: 110933. doi:10.1016/j.fct.2019.110933. ISSN 0278-6915. PMID 31682930.
  10. Zhang, Zhengfu; Guo, Ying; Zhang, Lingwei; Zhang, Jianbin; Wei, Xionghui (2012-10-01). "Chelerythrine chloride from Macleaya cordata induces growth inhibition and apoptosis in human gastric cancer BGC-823 cells". Acta Pharmaceutica Sinica B. 2 (5): 464–471. doi:10.1016/j.apsb.2011.12.013. ISSN 2211-3835.
  11. Yang, Rosania; Tavares, Maurício T.; Teixeira, Sarah F.; Azevedo, Ricardo A.; C Pietro, Diego; Fernandes, Thais B.; Ferreira, Adilson K.; Trossini, Gustavo H. G.; Barbuto, José A. M.; Parise-Filho, Roberto (1 October 2016). "Toward chelerythrine optimization: Analogues designed by molecular simplification exhibit selective growth inhibition in non-small-cell lung cancer cells". Bioorganic & Medicinal Chemistry. 24 (19): 4600–4610. doi:10.1016/j.bmc.2016.07.065. ISSN 1464-3391. PMID 27561984.
  12. Saavedra, Ana; Fernández-García, Sara; Cases, Silvia; Puigdellívol, Mar; Alcalá-Vida, Rafael; Martín-Flores, Núria; Alberch, Jordi; Ginés, Silvia; Malagelada, Cristina; Pérez-Navarro, Esther (April 2017). "Chelerythrine promotes Ca2+-dependent calpain activation in neuronal cells in a PKC-independent manner". Biochimica et Biophysica Acta (BBA) - General Subjects. 1861 (4): 922–935. doi:10.1016/j.bbagen.2017.01.021. ISSN 0304-4165. PMID 28130160.
  13. Vieira, Saulo Martins; de Oliveira, Vanessa Honorato; Valente, Raphael do Carmo; Moreira, Otacílio da Cruz; Fontes, Carlos Frederico Leite; Mignaco, Julio Alberto (2015-03-15). "Chelerythrine inhibits the sarco/endoplasmic reticulum Ca(2+)-ATPase and results in cell Ca(2+) imbalance". Archives of Biochemistry and Biophysics. 570: 58–65. doi:10.1016/j.abb.2015.02.019. ISSN 1096-0384. PMID 25721495.
  14. He, Nan; Wang, Peiqing; Wang, Pengyu; Ma, Changyang; Kang, Wenyi (2018-09-26). "Antibacterial mechanism of chelerythrine isolated from root of Toddalia asiatica (Linn) Lam". BMC Complementary and Alternative Medicine. 18 (1): 261. doi:10.1186/s12906-018-2317-3. ISSN 1472-6882. PMC 6158911. PMID 30257662.


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