Chemistry:Cynaropicrin

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Cynaropicrin is a sesquiterpene lactone of the guaianolide type found mainly in leaves of artichoke plants. It is one of the compounds that gives the artichoke its characteristic bitterness. It is found in artichoke leaves with an abundance of approximately 87 g/kg, but can hardly be found in other parts of the plant.[1] Cynaropicrin makes up about 0.7% of leaf extracts of the artichoke. It exhibits a large diversity of bioactivities and shows properties such as anti-inflammatory, antifeedant and activation of bitter sensory receptors,[2] but has not yet been used in medicine. Despite its pharmacologically beneficial properties, it can be toxic in higher doses. The compound has attracted attention in recent years as a potential anticancer drug.[3]

History

The knowledge of the health benefits of the artichoke dates back to the 4th century B.C., but its use was not rediscovered until the 16th century. Research into the composition of the artichoke started in the first half of the 20th century. In the early 1950s, cynarin was isolated from the leaves and some years later cynaropicrin was discovered.[4] Cynaropicrin was first isolated from the leaves of the Cynara scolymus L. (artichoke) in 1959 by a group of researchers of the Czechoslovak Academy of Sciences in Prague. It was found to be the main compound causing the bitter flavour of the artichoke. The researchers encountered difficulties in acquiring cynaropicrin in a crystalline form, which they later found to be caused by its ability to readily polymerize.[5]

Structure and reactivity

Cynaropicrin has a 5-7-5 fused tricyclic skeleton and contains two hydroxyl groups on each side of the molecule, allowing it to form a homopolymer. Its γ-butyrolactone ring is involved in most of its biological functions. The unsaturated carbonyl group on the lactone ring allows for nucleophilic Michael addition. Cynaropicrin is soluble in water and has no violations of the rule of five.[2]

Synthesis

Cynaropicrin is synthesized in the leaves of the artichoke plant and was found to accumulate in the trichomes.[6] While the full mechanism of biosynthesis of cynaropicrin is unknown, it is proposed that biosynthesis starts with three isoprene C5-units, which are processed by the mevalonate pathway to form farnesyl pyrophosphate (FPP). With germacrene A and germacrene A acid as intermediates, FPP is converted into costunolide using two syntheses and a cytochrome P450 oxidase. Multiple yet unknown reactions occur to first form guaianolide and later cynaropicrin.[2][6][7]

Mechanism of action

Cynaropicrin is shown to have various effects, and thus various mechanisms of action.

Anti-Hepatitis C virus

Cynaropicrin inhibits the entry of pan-genomic Hepatitis C virus into cells and inhibits cell-cell transmission.[8]

Anti-hyperlipidemic

Cynaropicrin also shows anti-hyperlipidemic activity. The oxygen functional groups and the methylene of the GBL ring were found the help in anti-hyperlipidemic activity. Inhibition of gastric emptying also plays a minor role in this property.[9]

Anti-tumor and cytotoxic activity

Cynaropicrin inhibits the activation of major adhesion molecules CD29 and CD98 involved in inflammation, but not CD43. This indicates that it might be a specific immunopharmacological effect. These adhesion molecules are essential factors in regulating the inflammatory process. It is linked to the inhibition of extracellular signal-related kinase (ERK).[10]

Research shows that it had a pro-apoptotic activity on cancer cell lines U937, Eol-1 and Jurkat T cells. Its cytotoxic activity was inhibited by N-acetyl-L-cysteine and L-cysteine, reactive oxygen species and rottlerin (protein kinase Cδ inhibitor), indicating that PKCδ and ROS are important for its pro-apoptotic activity of cynaropicrin by proteolytic cleavage of PKCδ.[11]

Transcription factor ‘Signal inducer and activator of transcription 3’ (STAT3) is continuously activated in cancer cells. It plays a critical role in the inhibition of apoptosis and induces chemoresistance. The α-β-unsaturated carbonyl moiety in cynaropicrin leads to a drop of intracellular GSH concentration via the Michael reaction. This inhibits the phosphorylation of STAT3 and increases the S-glutathionylation of STAT3 and therefore deactivating it. This leads to an increase in the expression of apoptotic genes.[12]

Anti-inflammatory

Cynaropicrin is an inhibitor of TNF-α, a cytokine used in inflammation of tissue. It inhibits the production of TNF-α from lipopolysaccharide-stimulated murine macrophage RAW264.7 cells. It also inhibits the release of nitric oxide from lipopolysaccharide- and interferon-γ-stimulated RAW264.7 cells. Lastly. it also suppressed lymphocyte proliferation from splenocytes. All these compounds, TNF-α, nitric oxide and lymphocytes, are all essential for inflammation.[2]

Anti-photoaging and Antioxidant

Cynaropicrin is a potent activator of the ArH-Nrf2-Nqo1 pathway in human keratinocytes. It also inhibits the generation of ROS, and pro-inflammatory cytokines TNF-α and IL-6 in keratinocytes irradiated with UVB. These processes are important in photoaging which is a causative agent for skin cancer.[2]

Antibacterial

Cynaropicrin binds to the thiol group of the Cys115 in the bacterial enzyme MurA through Michael addition reaction. The unsaturated ester side chain of cynaropicrin appears to mimic the substrate phosphoenolpyruvate (PEP). The irreversible inhibition of this enzyme stops the cytoplasmic biosynthesis of peptidoglycan precursor molecules.[2]

Anti-parasitic

Cynaropicrin shows a reduction in parasitemia in murine models and has potent antitrypanosomal activity. It lowers intracellular GSH and trypanothione levels and inhibits trypanosomal ornithine decarboxylase with its α,β-unsaturated methylene moiety which acts as Michael acceptor. This leads to apoptosis of parasites. The 2-hydroxymethyl-2-propenoyl moiety was found to play an important role in the toxicity. Removal of this group led to a loss of toxicity towards T. brucei rhodesiense and a tenfold loss of activity against T brucei.[2]

Metabolism

The metabolism of cynaropicrin and the biotransformation in humans is not known.

Indications

Anti-Hepatitis C virus

Cynaropicrin has been shown to be an inhibitor against HCV in the early stages of its lifecycle. Eight of the eighteen[13] genotypes of the HCV virus (1a, 1b, 2b, 3a, 4a, 5a, 6a, and 7a) were inhibited using only small doses, revealing its potential against the disease.[2]

Anti-hyperlipidemic

It was shown that leaf-extract of artichoke, with cynaropicrin as one of its functional compounds, put a restraint on the elevation of serum triglyceride elevation. This raises the possibility of the use against obesity related diseases and up to now incurable diseases.[2]

Anti-tumor and Cytotoxic activity

Cynaropicrin has a cytotoxic effect in various human cancer cell lines. It has been shown to inhibit cell proliferation in certain cancer cell lines (AGS and Hepa 1c1c7 cells), which is possible by, among other things, suppression of anti-apoptotic genes.[14] It also induces apoptosis in leukocyte cancer cells and affects the invasion, migration and metastasis of those cells. This is an example of diseases mediated by DC29 and DC98, of which the compound holds potential as a drug for treatment.[2]

Anti-inflammatory

Cynaropicrin has anti-inflammatory abilities through the proliferation of lymphocytes and the inhibition of the production of mediators. An example of which is the inhibition of cytokine-induced and TNF-α neutrophil chemoattractant-1 and nitric oxide release.[2]

Anti-photoaging and Antioxidant

Cynaropicrin can be used as an anti-photoaging agent, as it prevents UVB-induced photoaging. Additionally, an experiment with artichoke leaf extract resulted in a decrease in wrinkles and noticeable pores, as well as an increase in facial pigmentation. This is due to the lessened decline of dermal proteoglycan, a compound important for holding water.[2]

Antibacterial

In bacterial cells the enzyme MurA is of vital importance, as it is responsible for the cytoplasmic biosynthesis of peptidoglycan precursor molecules. Cynaropicrin inhibits this enzyme, and thus it has potent antibacterial activity.[2]

Anti-parasitic

It has been shown that cynaropicrin has anti-parasitic activities for various organisms (trypanosoma) both in vitro and in vivo. The compound is the first natural product that has in vivo potential against the T. brucei.[2]

Antifeedant

Cynaropicrin is a compound with promising potential as an antifeedant, as it has been shown to have deterring activity against multiple species of Lepidoptera (Arctiidae and Saturniidae). It also works relatively well against Trogoderma granarium larvae, Tribolium confusum larvae and Sitophilus granarius beetles.[2] The compound works the best in combination with other sesquiterpene lactones and not in its pure form.[15]

Efficacy

Anti-Hepatitis C virus

The effect of cynaropicrin on all affected genotypes has been shown to be generally strong, with EC50 values in low micromolar ranges: 0.4 - 1.4 μM, with an average of 0.8 μM.[8]

Anti-tumor and cytotoxic

Cynaropicrin has shown variable efficacy on different cancer cell lines. The IC50 lies between 0.068 and 8.7 μg/ml, with outliers of 30.22 and 116.96 μg/ml for the growth inhibition of AGS and Hepa1c1c7 cells respectively.[2]

The cytotoxic effect on some of the human tumor cell lines has been given contradictory ED50 values. SK-OV-3, SK-MEL-2, A549, HCT-15 and XF498 (CNS) cell lines have been tested and resulted in a range between 0.29 and 1.37 μg/ml. Another study has given values between 1.41 and 8.48 μg/ml for the SK-MEL-2, SK-OV-3, A549 and HCT cell lines. Additionally, the same study has given a range of ED50 values for the compound doxorubicin, which is 0.0038-0.089 μm/ml. This leaves cynaropicrin as the less effective compound.[2]

Anti-photoaging and Antioxidant

In keratinocytes, cynaropicrin has an EC50 of 0.89 μM and an CC50 of 47.6 μM on Nqo1 induction. This makes it a potent antioxidant there and thus a potent anti-photoaging compound.[2]

Anti-parasitic

For the antiparasitic activity of cynaropicrin various species were tested, especially the trypanosoma. The IC50 values vary, but lie between 0.2 and 4.4 μM. In a mouse model the compound caused a reduction of parasitemia of 92% in comparison to the control.[2]

Toxicity

The toxicity of cynaropicrin was investigated in vitro and in vivo. In mice, doses of 25 mg/kg/day increased the mortality and induced toxic effects like ataxia and tremors. At higher doses (≥200 mg/kg), the liver was also affected. There was an increase in the ALT levels, with effects of mononuclear cell infiltration, necrosis and hepatocyte regeneration. Additionally, the spleen undergoes a modest amount of white pulp activation and has an increased number of megakaryocytes. At a dose of 400 mg/kg, mice died due to its toxicity.[16]

It has been shown that cynaropicrin has a dose-related effect on cell cultures of neuronal and glial cells of foetal rat brain. The functionality of the compound is unknown, but results in cell death in more than eighty percent of the cells of the culture.[17]

On preparations of isolated aortic rings of rabbit it was shown that cynaropicrin inhibits the contraction of smooth muscles.[18]

In humans, there has been no proven toxicological effects in normal intake. However, when taken in pure form in large quantities, it is acutely toxic.[19] People who come into contact with the compound due to their profession sometimes develop the allergic reaction contact dermatitis[20] or local eczema.[4]

References

  1. ↑ Ramos, Patrícia A. B.; Guerra, Ângela R.; Guerreiro, Olinda; Freire, Carmen S. R.; Silva, Artur M. S.; Duarte, Maria F.; Silvestre, Armando J. D. (2013-08-21). "Lipophilic Extracts of Cynara cardunculus L. var. altilis (DC): A Source of Valuable Bioactive Terpenic Compounds". Journal of Agricultural and Food Chemistry 61 (35): 8420–8429. doi:10.1021/jf402253a. ISSN 0021-8561. PMID 23915287. 
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 2.17 2.18 Elsebai, Mahmoud Fahmi; Mocan, Andrei; Atanasov, Atanas G. (2016). "Cynaropicrin: a comprehensive research review and therapeutic potential as an anti- hepatitis C virus agent" (in English). Frontiers in Pharmacology 7: 472. doi:10.3389/fphar.2016.00472. ISSN 1663-9812. PMID 28008316. 
  3. ↑ Liu, Tianyu; Zhang, Junmin; Han, Xiao; Xu, Jianqiang; Wu, Yueting; Fang, Jianguo (2019-05-01). "Promotion of HeLa cells apoptosis by cynaropicrin involving inhibition of thioredoxin reductase and induction of oxidative stress" (in en). Free Radical Biology and Medicine 135: 216–226. doi:10.1016/j.freeradbiomed.2019.03.014. ISSN 0891-5849. PMID 30880248. http://www.sciencedirect.com/science/article/pii/S0891584919301030. 
  4. ↑ 4.0 4.1 Salem, Maryem Ben; Affes, Hanen; Ksouda, Kamilia; Dhouibi, Raouia; Sahnoun, Zouheir; Hammami, Serria; Zeghal, Khaled Mounir (2015-12-01). "Pharmacological Studies of Artichoke Leaf Extract and Their Health Benefits" (in en). Plant Foods for Human Nutrition 70 (4): 441–453. doi:10.1007/s11130-015-0503-8. ISSN 1573-9104. PMID 26310198. 
  5. ↑ Suchý, M.; Herout, V.; Šorm, F. (1960). "On terpenes. CVI. On hydrogenation products of cynaropicrin, the bitter principle of artichoke (Cynara scolymus L.)" (in en). Collection of Czechoslovak Chemical Communications 25 (2): 507–514. doi:10.1135/cccc19600507. ISSN 1212-6950. http://cccc.uochb.cas.cz/25/2/0507/. 
  6. ↑ 6.0 6.1 Eljounaidi, K.; Comino, C.; Moglia, A.; Cankar, K.; Genre, A.; Hehn, A.; Bourgaud, F.; Beekwilder, J. et al. (2015-10-01). "Accumulation of cynaropicrin in globe artichoke and localization of enzymes involved in its biosynthesis" (in en). Plant Science 239: 128–136. doi:10.1016/j.plantsci.2015.07.020. ISSN 0168-9452. PMID 26398797. http://www.sciencedirect.com/science/article/pii/S0168945215300261. 
  7. ↑ Menin, Barbara; Comino, Cinzia; Portis, Ezio; Moglia, Andrea; Cankar, Katarina; Bouwmeester, Harro J.; Lanteri, Sergio; Beekwilder, Jules (2012-07-01). "Genetic mapping and characterization of the globe artichoke (+)-germacrene A synthase gene, encoding the first dedicated enzyme for biosynthesis of the bitter sesquiterpene lactone cynaropicrin" (in en). Plant Science 190: 1–8. doi:10.1016/j.plantsci.2012.03.006. ISSN 0168-9452. PMID 22608514. http://www.sciencedirect.com/science/article/pii/S016894521200060X. 
  8. ↑ 8.0 8.1 Elsebai, Mahmoud Fahmi; Koutsoudakis, George; Saludes, Verónica; Pérez-Vilaró, Gemma; Turpeinen, Ari; Mattila, Sampo; Pirttilä, Anna Maria; Fontaine-Vive, Fabien et al. (2016-02-15). "Pan-genotypic Hepatitis C Virus Inhibition by Natural Products Derived from the Wild Egyptian Artichoke". Journal of Virology 90 (4): 1918–1930. doi:10.1128/JVI.02030-15. ISSN 1098-5514. PMID 26656684. 
  9. ↑ Shimoda, Hiroshi; Ninomiya, Kiyofumi; Nishida, Norihisa; Yoshino, Tomoe; Morikawa, Toshio; Matsuda, Hisashi; Yoshikawa, Masayuki (2003-01-20). "Anti-Hyperlipidemic sesquiterpenes and new sesquiterpene glycosides from the leaves of artichoke (Cynara scolymus L.): structure requirement and mode of action" (in en). Bioorganic & Medicinal Chemistry Letters 13 (2): 223–228. doi:10.1016/S0960-894X(02)00889-2. ISSN 0960-894X. PMID 12482428. http://www.sciencedirect.com/science/article/pii/S0960894X02008892. 
  10. ↑ Cho, Jae Youl; Kim, Ae Ra; Joo, Hong-Gu; Kim, Byung-hun; Rhee, Man Hee; Yoo, Eun Sook; Katz, David R.; Chain, Benjamin M. et al. (2004-01-23). "Cynaropicrin, a sesquiterpene lactone, as a new strong regulator of CD29 and CD98 functions". Biochemical and Biophysical Research Communications 313 (4): 954–961. doi:10.1016/j.bbrc.2003.12.026. ISSN 0006-291X. PMID 14706635. https://www.ncbi.nlm.nih.gov/pubmed?Db=pubmed&Cmd=ShowDetailView&TermToSearch=14706635. 
  11. ↑ Cho, Jae Youl; Kim, Ae Ra; Jung, Jee H.; Chun, Taehoon; Rhee, Man Hee; Yoo, Eun Sook (2004-05-25). "Cytotoxic and pro-apoptotic activities of cynaropicrin, a sesquiterpene lactone, on the viability of leukocyte cancer cell lines". European Journal of Pharmacology 492 (2–3): 85–94. doi:10.1016/j.ejphar.2004.03.027. ISSN 0014-2999. PMID 15178350. https://www.ncbi.nlm.nih.gov/pubmed?Db=pubmed&Cmd=ShowDetailView&TermToSearch=15178350. 
  12. ↑ Butturini, Elena; Carcereri de Prati, Alessandra; Chiavegato, Giulia; Rigo, Antonella; Cavalieri, Elisabetta; Darra, Elena; Mariotto, Sofia (December 2013). "Mild oxidative stress induces S-glutathionylation of STAT3 and enhances chemosensitivity of tumoural cells to chemotherapeutic drugs". Free Radical Biology & Medicine 65: 1322–1330. doi:10.1016/j.freeradbiomed.2013.09.015. ISSN 1873-4596. PMID 24095958. https://www.ncbi.nlm.nih.gov/pubmed?Db=pubmed&Cmd=ShowDetailView&TermToSearch=24095958. 
  13. ↑ Yu, Chun I.; Chiang, Bor-Luen (2010). "A New Insight into Hepatitis C Vaccine Development" (in en). Journal of Biomedicine and Biotechnology 2010: 548280. doi:10.1155/2010/548280. PMID 20625493. 
  14. ↑ Kang, Kyungsu; Lee, Hee Ju; Kim, Chul Young; Lee, Saet Byoul; Tunsag, Jigjidsuren; Batsuren, Dulamjav; Nho, Chu Won (2007). "The Chemopreventive Effects of Saussurea salicifolia through Induction of Apoptosis and Phase II Detoxification Enzyme". Biological & Pharmaceutical Bulletin 30 (12): 2352–2359. doi:10.1248/bpb.30.2352. ISSN 0918-6158. PMID 18057725. 
  15. ↑ Mander, Lewis N. Liu, Hung-wen, 1952- (2012). Comprehensive natural products II : chemistry and biology. Elsevier. ISBN 978-1-78034-559-8. OCLC 801865009. 
  16. ↑ Silva, Cristiane França da; Batista, Denise da Gama Jaen; Araújo, Julianna Siciliano De; Batista, Marcos Meuser; Lionel, Jessica; Souza, Elen Mello de; Hammer, Erica Ripoll; Silva, Patricia Bernardino da et al. (2013-11-01). "Activities of Psilostachyin A and Cynaropicrin against Trypanosoma cruzi In Vitro and In Vivo" (in en). Antimicrobial Agents and Chemotherapy 57 (11): 5307–5314. doi:10.1128/AAC.00595-13. ISSN 0066-4804. PMID 23939901. 
  17. ↑ CHENG, C; COSTALL, B; HAMBURGER, M; HOSTETTMANN, K; NAYLOR, R; WANG, Y; JENNER, P (March 1992). "Toxic effects of solstitialin a 13-acetate and cynaropicrin from Centaurea solstitialis L. (asteraceae) in cell cultures of foetal rat brain". Neuropharmacology 31 (3): 271–277. doi:10.1016/0028-3908(92)90177-q. ISSN 0028-3908. PMID 1630595. 
  18. ↑ Hay, Alastair J.B.; Hamburger, Matthias; Hostettmann, K.; Hoult, J.R.S. (May 1994). "Toxic inhibition of smooth muscle contractility by plant-derived sesquiterpenes caused by their chemically reactive α-methylenebutyrolactone functions". British Journal of Pharmacology 112 (1): 9–12. doi:10.1111/j.1476-5381.1994.tb13020.x. ISSN 0007-1188. PMID 8032668. 
  19. ↑ PubChem. "Cynaropicrin" (in en). https://pubchem.ncbi.nlm.nih.gov/compound/119093. 
  20. ↑ "Artochoke Extract For the Treatment of Dyspeptic Complaints". http://www.euromed.es/euromed/wp-content/uploads/2018/04/alcachofa_booklet.pdf. [yes|permanent dead link|dead link}}]



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