Chelidonine

Chelidonine
Names
IUPAC name
(5bR,6S,12bS)-13-Methyl-5b,6,7,12b,13,14-hexahydro-[1,3]dioxolo[4',5':4,5]benzo[1,2-c][1,3]dioxolo[4,5-i]phenanthridin-6-ol
Identifiers
476-32-4
3D model (Jmol) Interactive image
ChemSpider 171216
ECHA InfoCard 100.006.823
PubChem 197810
Properties
C20H19NO5
Molar mass 353.37 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

( Chelidonine is an isolate of Papaveraceae with acetylcholinesterase and butyrylcholinesterase inhibitory activity.

Introduction

Chelidonine is the major alkaloid component of Chelidonium majus. Chelidonium majus L. is the only species of the tribe Chelidonieae of the Papaveraceae family. The Papaveraceae family is rich in specific alkaloids. C. majus contains various isoquinoline alkaloids with protopine, protoberberine and benzophenanthridine structures.[1] This benzophenanthridine alkaloid can induce apoptosis in some transformed or malignant cell lines.[2]

D-Chelidonine, the main alkaloid of Chelidonium majus, was first isolated in 1839.[3] The healing properties of greater celandine (Chelidonium majus) were known throughout Europe and Asia during the Emperial Roman period (Pliny 1966), and New World aboriginal cultures exploited the antimicrobial effects of BIA-containing plants by using sap or root extracts to treat minor cuts and infections.[4]

Synthesis

The amide was heated in boiling bromobenzene to form the transfused compound. By contrast, thermolysis of the more flexible urethane afforded the desired cis fused product. The building blocks required for the synthesis of chelidonine are urathane and benzyl bromide. The urathane was obtained by first using nitrile, duo to hydrolysis carboxylic acid was generated. The carboxylic acid which on Curtius degradation yielded crude isocyanate (N=C=O). The reaction of crude isocyanate with benzyl alcohol made the urethane, with the NHCOOC7H7 side group. The benzyl bromide was obtained by the conversion of 2,3-methylenedioxybenzaldehyde to 1,2,3,4 - tetrahydro-7,8-methylenedioxyisoquinol by the successive Hofmann and von Braun degradations.[3]

Condensation of urethane and benzyl bromide led to the formation of the oily styrene. From this structure the liquid acetylene was formed. Next, the crystalline tetrahydrobenz[c]phenanthridine was formed. hydroboration and oxidation produced an alcohol. Jones oxidation gave rise to the ketone. And by processing the ketone the desired cis,cis-alcohol was formed. After hydrogenolysis of the benzyloxycarbonyl group, dl-norchelidonine was synthesized.[3]

Available forms

Chelidonine has a few forms which are synthesized in a similar way and which are structurally alike, including: (+)-homochelidonine, (+)-chelamine and (−)-norchelidonine are tertiary benzo[c]phenanthridine alkaloids with partially hydrogenated B and C rings. They occur in a number of plant species of the Papaveraceae family. The first two have been isolated from the roots of Chelidonium majus L. as minor alkaloids. Enantiomeric (+)-norchelidonine has been recently found in C. majus.[5]

Mechanisms of action

Chelidonine has been found to be a potential anti-cancer medicine. Although there seem to be many different pathways and functional parts of the molecule. Chelidonine can induce mitotic slippage and apoptotic-like cell death.[6] There are several pathways in which chelidonine has an inhibitory function.

For example, chelidonine can inhibit the IPP-complex and subsequent down-regulation of IPP downstream signaling molecules, like Akt and ERK1/2. This suggests that chelidonine may be a potential agent against metastasis of invasive human cancer cells.[7]

Also, chelidonine showed strong cytotoxicity in cancer cells. It strongly inhibits telomerase and stimulates multiple mechanisms including apoptosis, autophagy and senescence. This make it a potential suppressor of cancer cell growth.[8]

The mechanism through which chelidonine achieved its anti-cancer potential was by inducing apoptosis in cancer cells through activation of the p38-p53-dependent pathway on one hand, and through inhibitory influence on the proliferating ability of the cells by down-regulating the JAK-STAT and AKT pathway on the other.[9]

Cancer cells often develop multidrug resistance (MDR), which involves several mechanisms and targets. Chelidonine has the ability to overcome MDR of different cancer cell lines through interaction with ABC-transporters by induction of apoptosis and cytotoxic effects, which makes chelidonine a promising model compound for overcoming MDR and enhancing the cytotoxicity of chemotherapeutics, especially against leukaemia cells. Its efficacy needs to be confirmed in animal models.[10]

Metabolism

Chelidonine is a major bioactive, isoquinoline alkaloid ingredient in Chelidonium majus. Benzylisoquinoline alkaloids (BIAs) are a structurally diverse group of plant specialized metabolites with a long history of investigation. A restricted number of enzyme families have been implicated in BIA metabolism. Whereas some enzymes exhibit a relatively broad substrate range, others are highly substrate specific.

A small number of plant species, including opium poppy (Papaver somniferum) and other members of the Ranunculales, have emerged as model systems to study BIA metabolism. Recently, the emergence of transcriptomics, proteomics and metabolomics has expedited the discovery of new BIA biosynthetic genes.

In general, methyltransferases of BIA metabolism accept a wide variety of alkaloid substrates with diverse backbone structures, with some showing more flexibility than others with respect to substrate range.[4]

Indications

Chelidonine is an isolate of Papaveraceae with acetylcholinesterase and butyrylcholinesterase (a nonspecific cholinesterase) inhibitory activity. AChE (acetylcholinesterase) inhibitors or anti-cholinesterases inhibit the cholinesterase enzyme from breaking down ACh, increasing both the level and duration of the neurotransmitter action. According to the mode of action, AChE inhibitors can be divided into two groups: irreversible and reversible.

Reversible inhibitors, competitive or noncompetitive, mostly have therapeutic applications, while toxic effects are associated with irreversible AChE activity modulators. Reversible AChE inhibitors play an important role in pharmacological manipulation of the enzyme activity. These inhibitors include compounds with different functional groups (carbamate, quaternary or tertiary ammonium group), and have been applied in the diagnostic and/or treatment of various diseases such as: myasthenia gravis, AD, post-operative ileus, bladder distention, glaucoma, as well as antidote to anticholinergic overdose.[11]

Efficacy and side effects

Chelidonine exhibits a broad spectrum of pharmacological properties, such as anti-inflammatory and antiviral activities.[12] Its biological activities an clinical applications have been extensively investigated. Especially the usage of chelidonine (or substances alike) as an anticancer drug is very important lately. It also has profound inhibitory effects on airway inflammation, which means chelidonine can improve allergic asthma in mice and may also work for human medicine.[7] Chelidonine could also be useful to reduce cadmium induced nephrotoxicity, this has been studied in rats.[13]

Toxicity

Chelidonine has been studied in multiple organisms, but mainly in rats and mice. In these organisms, sublethal doses of chelidonine caused ptosis tremor, sedation, and a decrease in body temperature. The LD50 of chelidonine, intraperitoneally administered, is in mice 1.3 g/kg and in rats 2 g/kg.[14] There are not many studies of toxicity of chelidonine in humans.

Animals

In 1968 Chelidonine was already tested in vivo on mice with various tumours. Although effective, chelidonine caused considerable toxic side effects at therapeutic doses. However, the drug Ukrain, which is a semisynthetic substance derived from Chelidonine, is reported to be selectively toxic to malignant cells, and apparently has no toxic side effects when used as a chemotherapeutic drug.[15]

A good model to assess in vivo effects on stem cell dynamics of natural and synthetic substances are planarian flatworms. In these animals, adult pluripotent stem cells as well as fast regenerative capabilities are present. Chelidonine produces a significant anti-proliferative effect on planarian stem cells in a dose dependent fashion. Mitotic abnormalities were also observed and the number of cells able to proceed to the anaphase/telophase was significantly reduced. This could indicate that chelidonine acts on cell cycle progression by inhibition of tubulin polymerization.[16]

References

  1. ↑ Bosisio, E. (1996). Pharmacological activities of Chelidonium majus L. (Papaveraceae). Elsevier, 33(2), 127-134.
  2. ↑ Kemeny-Beke, A., Aradi, J., Beck, Z., Facsko, A., Berta, A., & Bodnar, A. (2006). Apoptotic response of uveal melanoma cells upon treatment with chelidonine, sanguinarine and chelerythrine. Elsevier, 237(1), 67-75.
  3. 1 2 3 Keller, K. (1971). Total synthesis of dl-chelidonine. Journal of the American Chemical Society, 117(51), 3836.
  4. 1 2 Hagel, J. M, & Facchini, P. J. (2013). Benzylisoquinoline Alkaloid Metabolism: A Century of Discovery and a Brave New World. Plant and Cell Physiology, 1(26), 4.
  5. ↑ Necas, M., Dostal, J., Kejnovska, I., Vorlickova, M., & Slavik, J. (2005). Molecular and crystal structures of (+)-homochelidonine, (+)-chelamine, and (−)-norchelidonine. Journal of Molecular Structure, 734(1-3), 1-6.
  6. ↑ Qu, Z., Zou, X., Zhang, X., Sheng, J., Wang, Y., Wang, J., . . . Ji, Y. (2016). Chelidonine induces mitotic slippage and apoptotic-like death in SGC-7901 human gastric carcinoma cells. Mol Med Rep(Feb 13(2)), 1336-1344.
  7. 1 2 Kim, O., Hwangbo, C., Kim, J., Li, D., Min, B., & Lee, J. (2015). Chelidonine suppresses migration and invasion of MDA-MB-231 cells by inhibiting formation of the integrin-linked kinase/PINCH/α-parvin complex. Mol Med Rep, 2015 Aug(12(2)), 2161-2168.
  8. ↑ Noureini, S., & Esmaili, H. (2014). Multiple mechanisms of cell death induced by chelidonine in MCF-7 breast cancer cell line. Chemico-Biological Interactions, 223 (5 Nov 2014), 141-149.
  9. ↑ Paul, A., Bishayee, K., Ghosh, S., Mukherjee, A., Sikdar, S., Chakraborty, D., Khuda-Bukhsh, A. (2012). Chelidonine isolated from ethanolic extract of CHelidonium majus promotes apoptosis in HeLa cells through p38-p53 and PI3K/AKT signalling pathways. Journal of Chinese integrative Medicine, Sept 2012(10(9)), 1025-1038.
  10. ↑ El-Raedi, M., Eid, S., Ashour, M., Tahrani, A., & Wink, M. (2013). Modulation of multidrug resistance in cancer cells by chelidonine and Chelidonium majus alkaloids. Phytomedicine, 20(3-4), 282-294.
  11. ↑ Colovic, M. B. (2013). Acetylcholinesterase Inhibitors: Pharmacology and Toxicology. Current Neuropharmacology, 11(3), 315-335.
  12. ↑ Seung-Hyung, K. (2015). Chelidonine, a principal isoquinoline alkaloid of Chelidonium majus, attenuates eosinophilic airway inflammation by suppressing IL-4 and eotaxin-2 expression in asthmatic mice. Pharmacological Reports, 67(6), 1168-1177.
  13. ↑ Koriem, K., Arbid, M., & Asaas, G. (2013). Chelidonium majus leaves methanol extract and its chelidonine alkaloid ingredient reduce cadmium-induced nephrotoxicity in rats. J Nat Med, 2013 Jan(67(1)), 159-167.
  14. ↑ Gardner, Z. (2013). American Herbal Products Association’s Botanical Safety Handbook (2e ed.). New York, America: CRC Press.
  15. ↑ Panzer, A. (2001). The effects of chelidonine on tubulin polymerisation, cell cycle progression and selected signal transmission pathways. European Journal of Cell Biology, 80(1), 111-118.
  16. ↑ Isolani, M., Pietra, D., Balestrini, L., Borghini, A., Deri, P., Imbriani, M., . . . Balestoni, R. (2012). The in vivo effect of chelidonine on the stem cell system of planarians. European Journal of Pharmacology, 686(1-3), 1-7.
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