Chelerythrine

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Chelerythrine
Chelerythrine.png
Chelerythrine 3D ball.png
Names
Preferred IUPAC name
1,2-Dimethoxy-12-methyl-9H-[1,3]benzodioxolo[5,6-c]phenanthridin-12-ium
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.047.194 OOjs UI icon edit-ltr-progressive.svg
PubChem CID
UNII
  • InChI=1S/C21H18NO4/c1-22-10-16-13(6-7-17(23-2)21(16)24-3)14-5-4-12-8-18-19(26-11-25-18)9-15(12)20(14)22/h4-10H,11H2,1-3H3/q+1 Yes check.svgY
    Key: LLEJIEBFSOEYIV-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C21H18NO4/c1-22-10-16-13(6-7-17(23-2)21(16)24-3)14-5-4-12-8-18-19(26-11-25-18)9-15(12)20(14)22/h4-10H,11H2,1-3H3/q+1
    Key: LLEJIEBFSOEYIV-UHFFFAOYAP
  • O1c3c(OC1)cc2ccc4c5c(c[n+](c4c2c3)C)c(OC)c(OC)cc5
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).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

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]

Contents

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]

Research

Antibacterial agent

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. [6]

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. [7] [8] In triple-negative breast cancer cells, this molecule is found to induce apoptosis. Nuclear fragmentation and chromatin condensation is observed, which is indicative of apoptosis. [9]

Other

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. [10] [11] 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. [12] [13] [14] 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. [15]

Anti-cancer mechanisms

Depending on the form of cancer, chelerythrine can exhibit different effects on tumor cells, leading to inhibition of tumor growth. These mechanisms include inducing apoptosis, arrest of the cell cycle, promoting autophagy of cancerous cells, and the inhibition of telomerase. It has been found to be a possible anti-cancer agent for liver, gastric, breast, renal, and cervical cancers. [16] Despite these claims, it is important to note that the related compound sanguinarine is associated with severe adverse effects. This is insufficient evidence to endorse the usage of chelerythrine present in botanical products as a cancer treatment.

Role as a protein kinase C inhibitor

Studies show that chelerythrine is a specific and potent protein kinase C inhibitor. Due to its inhibitory effects on protein kinase C, it has been found of use against triple-negative breast cancer. By inhibiting protein kinase C, signaling pathways are disrupted, inducing cell cycle arrest. [17]

Related Research Articles

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References

  1. ↑ Chelerythrine Chloride 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. S2CID   32722743.
  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. ↑ 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.
  7. ↑ 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.
  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. ↑ Lin, Wanjun; Huang, Jiajun; Yuan, Zhongwen; Feng, Senling; Xie, Ying; Ma, Wenzhe (2017-05-17). "Protein kinase C inhibitor chelerythrine selectively inhibits proliferation of triple-negative breast cancer cells". Scientific Reports. 7 (1): 2022. doi: 10.1038/s41598-017-02222-0 . ISSN   2045-2322. PMC   5435721 . PMID   28515445. S2CID   20299447.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ Chen, Nianzhi; Qi, Yulin; Ma, Xiao; Xiao, Xiaolin; Liu, Qingsong; Xia, Ting; Xiang, Juyi; Zeng, Jinhao; Tang, Jianyuan (2022). "Rediscovery of Traditional Plant Medicine: An Underestimated Anticancer Drug of Chelerythrine". Frontiers in Pharmacology. 13: 906301. doi: 10.3389/fphar.2022.906301 . ISSN   1663-9812. PMC   9198297 . PMID   35721116.
  17. ↑ Lin, Wanjun; Huang, Jiajun; Yuan, Zhongwen; Feng, Senling; Xie, Ying; Ma, Wenzhe (2017-05-17). "Protein kinase C inhibitor chelerythrine selectively inhibits proliferation of triple-negative breast cancer cells". Scientific Reports. 7 (1): 2022. doi: 10.1038/s41598-017-02222-0 . ISSN   2045-2322. PMC   5435721 . PMID   28515445. S2CID   20299447.
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