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Xanthatin

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Xanthatin
Identifiers
  • (3aR,7S,8aS)-7-methyl-3-methylidene-6-[(E)-3-oxobut-1-enyl]-4,7,8,8a-tetrahydro-3aH-cyclohepta[b]furan-2-one
CAS Number
PubChem CID
ChemSpider
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC15H18O3
Molar mass246.306 g·mol−1
3D model (JSmol)
  • CC1CC2C(CC=C1C=CC(=O)C)C(=C)C(=O)O2
  • InChI=InChI=1S/C15H18O3/c1-9-8-14-13(11(3)15(17)18-14)7-6-12(9)5-4-10(2)16/h4-6,9,13-14H,3,7-8H2,1-2H3/b5-4+/t9-,13+,14-/m0/s1

Xanthatin, or (3aR,7S,8aS)-7-methyl-3-methylidene-6-[(E)-3-oxobut-1-enyl]-4,7,8,8a-tetrahydro-3aH-cyclohepta[b]furan-2-one (C15H18O3) is a major bioactive compound found in the leaves of the Xanthium strumarium (Asteracae) plant. It is classified as a natural sesquiterpene lactone. Xanthatin is believed to have anti-inflammatory, anti-tumour, anti-microbial, and anti-parasitic properties hence it is being researched for potential use in treatment of cancer and autoimmune diseases. While it has been used in traditional medicine for decades, its mechanisms and modern use haven’t been fully understood yet.

History

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Traditional usage

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Xanthium strumarium L. (Asteracae) has been used thousands of years as Chinese herbal medicine (named Cangerzi). Its leaves have shown anti-inflammatory, analgesic, anti-asthmatic, anti-microbial, and diuretic properties in an herbal supplement before it was known that xanthatin was the main bioactive compound.

In 1963, the fruits of Xanthium strumarium L. were listen in the Pharmacopoeia of the People’s Republic of China.[1]

Modern usage

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In 1975, xanthatin was isolated from the leaves of the Xanthium strumarium and it was determined to be the predominant compound in these plant leaves.[2] In the 21st century, in vitro, and in vivo research is performed on xanthatin showing promising results in anti-tumour, anti-inflammatory and antibacterial applications on various cell lines.[3][4][5][6][7][8][9][10][11]

Structure

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Xanthatin is a sesquiterpene lactone. It consists of three isoprene units with a lactone ring attached resulting in a sesquiterpene derivative[12] of C15H18O3 compared to the usual C15H18. During the synthesis of Xanthatin[13] it was reported that a multitude of functional groups could be derived from the same synthetic pathway showing much promise for other medicinal candidates.

Synthesis

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Xanthatin was first reported to be enantioselective synthesized by Shishido.[14] Further developments have shown that the synthesis can be adapted to form other xanthanolide analogues, which could be of medicinal interest. Many reaction steps are involved in the synthesis of Xanthatin a general overview is given with details below based on the research of Bergman et al.[13]

Methyl-furoate (1) is the commercially available starting compound used. To form the ketone group and prepare seven membered ring formation asymmetric catalytic cyclopropanation, ozonolysis is used followed by allylation, realdolation and lactonization. An apple type reaction a chemoselective reduction of the aldehyde formed is used to form 2.

Knochel’s protocol is used to provoke sp3-sp3 coupling with tert-butyl-2-(bromomethyl)acrylate after which the compound is used as a substrate in a ring closing metathesis reaction under influence of a Grubbs II catalyst. Giving rise to the bicyclic sesquiterpene skeleton of Xanthatin (3).

In order to form Xanthatin, more steps have to be executed. Due to the chair conformation of 3 it is sterically favored to form a single stereomere by execution of a Ene-reaction. The alcohol or ester that is formed can be removed by presence of CuCN and RLi in a SN2 like fashion. 

The final steps include the formation of a α-exo-methylene group at the C-3 position. The α-exo-methylene group introduction is a difficult process since the molecule is already prone to unwanted side reactions. In order to achieve this a method involving base induced hydroxymethylation by gaseous formaldehyde following a pivalylation introduced a methanol group at the C-3. The tert-butylester needs to be stepwise hydrolysed towards an aldehyde. When the molecule was introduced to a strong base the desired α-exo-methylene-γ-butyrolactone group was formed. A Makaiyama aldol condensation with trimethyl(prop-1-en-2-yloxy)silane is added for the complete synthesis of Xanthatin and its derivatives

Mechanism of action

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The exact mechanism of action of xanthatin is not exactly known. However, it was found that it works through various molecular pathways which all lead to apoptosis. One of these proposed pathways is that xanthatin inhibits the nuclear factor-kappa B (NF-κB) transcription factor which is critical for controlling cell proliferation.[15] This would reduce inflammation and suppress growth of cancer cells. Another study suggests the same with addition of induced endoplasmic reticulum (ER) stress in glioma (brain cancer) which also leads to apoptosis.[16] Oxidative stress is another pathway in which xanthatin works. It binds to selenocysteine (Sec) residue of TrxR enzyme which leads to irreversible inhibition. This leads to oxidative stress which can induce apoptosis.[17]

Metabolism

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Xanthatin is classified as a sesquiterpene lactone,[11] which can help to determine the metabolism of xanthatin, because metabolism of xanthatin is unknown. There are studies about the metabolism of different sesquiterpene lactones. Most of the sesquiterpene lactones are BCS II classified, which means that they have high permeability and low water solubility. After they entered the gastrointestinal tract, the absorption is poorly due to their pH sensitivity. Xanthatin contains a α-methylene-γ-butyrolactone, which is the main location of metabolism in other sesquiterpene lactones. However, there are metabolic differences in similar compounds with this reactive group. But phase I reactions such as oxidation, (de)hydration, hydroxylation, sequential desaturation, and epoxidation are found in different sesquiterpene lactones. (Acetyl)cysteine conjugation, methylation, glutathione conjugation are common phase II reactions in sesquiterpene lactones.[11]

Indications

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In traditional medicine, some symptoms may occur at high doses. These may include vomiting, tremors, weak pulse, a loss of appetite, and convulsions.[18]

Efficacy

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Traditionally, Xanthatin has been used in folk medicine. Xanthatin is a bioactive compound and possesses anti-inflammatory, analgesic, anti-asthmatic, anti-microbial, diuretic properties. However, scientific research of xanthatin is limited.

Scientific studies show that xanthatin can be anti-proliferative against various tumour cells in-vitro and in-vivo through inhibition and induce apoptosis.[3][19][20] Xanthatin also consists of an anti-inflammatory activity by inhibiting PGE2 synthesis and 5-lipoxygenase activity.[10]

Side effects

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Research data about side effects has not been reported due to lack of human data.

Toxicity

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At high concentrations, xanthatin exhibits hepatotoxic effects, causing liver damage in mice.[8] Xanthatin has been reported to promote apoptosis. Thus, this will also include cell proliferation of healthy tissue. In vitro, and in vivo research has shown that it can also cause DNA damage in regular cells.[21]

References

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  1. ^ International Trade Centre (January 2017). "MAPs listed in Pharmacopoeia of the People's Republic of China". Sustainable Sourcing. United Nations. doi:10.18356/94ce75d8-en. ISBN 9789213614266.
  2. ^ McMillan C, Chavez PI, Mabry TJ (October 1975). "Sesquiterpene lactones of Xanthium strumarium in a texas population and in experimental hybrids". Biochemical Systematics and Ecology. 3 (3): 137–141. Bibcode:1975BioSE...3..137M. doi:10.1016/0305-1978(75)90017-4.
  3. ^ a b Tao L, Fan F, Liu Y, Li W, Zhang L, Ruan J, et al. (2013-11-28). Afarinkia K (ed.). "Concerted suppression of STAT3 and GSK3β is involved in growth inhibition of non-small cell lung cancer by Xanthatin". PLOS ONE. 8 (11): e81945. Bibcode:2013PLoSO...881945T. doi:10.1371/journal.pone.0081945. PMC 3842975. PMID 24312384.
  4. ^ Sato Y, Oketani H, Yamada T, Singyouchi K, Ohtsubo T, Kihara M, et al. (October 1997). "A xanthanolide with potent antibacterial activity against methicillin-resistant Staphylococcus aureus". The Journal of Pharmacy and Pharmacology. 49 (10): 1042–1044. doi:10.1111/j.2042-7158.1997.tb06038.x. PMID 9364417. S2CID 208616559.
  5. ^ Tao L, Sheng X, Zhang L, Li W, Wei Z, Zhu P, et al. (September 2016). "Xanthatin anti-tumor cytotoxicity is mediated via glycogen synthase kinase-3β and β-catenin". Biochemical Pharmacology. 115: 18–27. doi:10.1016/j.bcp.2016.06.009. PMID 27321043.
  6. ^ Tao L, Cao Y, Wei Z, Jia Q, Yu S, Zhong J, et al. (December 2017). "Xanthatin triggers Chk1-mediated DNA damage response and destabilizes Cdc25C via lysosomal degradation in lung cancer cells". Toxicology and Applied Pharmacology. 337: 85–94. doi:10.1016/j.taap.2017.10.015. PMID 29074359. S2CID 32799679.
  7. ^ Ramírez-Erosa I, Huang Y, Hickie RA, Sutherland RG, Barl B (November 2007). "Xanthatin and xanthinosin from the burs of Xanthium strumarium L. as potential anticancer agents". Canadian Journal of Physiology and Pharmacology. 85 (11): 1160–1172. doi:10.1139/Y07-104. PMID 18066118.
  8. ^ a b Takeda S, Nishimura H, Koyachi K, Matsumoto K, Yoshida K, Okamoto Y, et al. (2013). "(-)-Xanthatin induces the prolonged expression of c-Fos through an N-acetyl-L-cysteine (NAC)-sensitive mechanism in human breast cancer MDA-MB-231 cells". The Journal of Toxicological Sciences. 38 (4): 547–557. doi:10.2131/jts.38.547. PMID 23824011.
  9. ^ Li WD, Wu Y, Zhang L, Yan LG, Yin FZ, Ruan JS, et al. (July 2013). "Characterization of xanthatin: anticancer properties and mechanisms of inhibited murine melanoma in vitro and in vivo". Phytomedicine. 20 (10): 865–873. doi:10.1016/j.phymed.2013.03.006. PMID 23664560.
  10. ^ a b Yoon JH, Lim HJ, Lee HJ, Kim HD, Jeon R, Ryu JH (March 2008). "Inhibition of lipopolysaccharide-induced inducible nitric oxide synthase and cyclooxygenase-2 expression by xanthanolides isolated from Xanthium strumarium". Bioorganic & Medicinal Chemistry Letters. 18 (6): 2179–2182. doi:10.1016/j.bmcl.2007.12.076. PMID 18276135.
  11. ^ a b c Nibret E, Youns M, Krauth-Siegel RL, Wink M (December 2011). "Biological activities of xanthatin from Xanthium strumarium leaves". Phytotherapy Research. 25 (12): 1883–1890. doi:10.1002/ptr.3651. PMID 21953905. S2CID 9556724.
  12. ^ Zhang J, Zhao R, Jin L, Pan L, Lei D (November 2022). "Xanthanolides in Xanthium L.: Structures, Synthesis and Bioactivity". Molecules. 27 (23): 8136. doi:10.3390/molecules27238136. PMC 9735877. PMID 36500229.
  13. ^ a b Bergmann A, Reiser O (June 2014). "Enantioselective synthesis of xanthatin". Chemistry: A European Journal. 20 (25): 7613–7615. doi:10.1002/chem.201402735. PMID 24823713.
  14. ^ Yokoe H, Yoshida M, Shishido K (May 2008). "Total synthesis of (−)-xanthatin". Tetrahedron Letters. 49 (21): 3504–3506. doi:10.1016/j.tetlet.2008.03.081.
  15. ^ Zhang L, Tao L, Ruan J, Li W, Wu Y, Yan L, et al. (June 2012). "Xanthatin induces G2/M cell cycle arrest and apoptosis in human gastric carcinoma MKN-45 cells". Planta Medica. 78 (9): 890–895. doi:10.1055/s-0031-1298481. PMID 22532019. S2CID 206328084.
  16. ^ Ma YY, Di ZM, Cao Q, Xu WS, Bi SX, Yu JS, et al. (March 2020). "Xanthatin induces glioma cell apoptosis and inhibits tumor growth via activating endoplasmic reticulum stress-dependent CHOP pathway". Acta Pharmacologica Sinica. 41 (3): 404–414. doi:10.1038/s41401-019-0318-5. PMC 7468336. PMID 31700088.
  17. ^ Liu R, Shi D, Zhang J, Li X, Han X, Yao X, Fang J (August 2018). "Xanthatin Promotes Apoptosis via Inhibiting Thioredoxin Reductase and Eliciting Oxidative Stress". Molecular Pharmaceutics. 15 (8): 3285–3296. doi:10.1021/acs.molpharmaceut.8b00338. PMID 29939757. S2CID 49415781.
  18. ^ "Pilot Case Control Study of Chinese Herbs and Liver Toxicity". Drug Safety. 31 (10): 885–960. 2008. doi:10.2165/00002018-200831100-00060. ISSN 0114-5916. S2CID 67992475.
  19. ^ Fan W, Fan L, Peng C, Zhang Q, Wang L, Li L, et al. (January 2019). "Traditional Uses, Botany, Phytochemistry, Pharmacology, Pharmacokinetics and Toxicology of Xanthium strumarium L.: A Review". Molecules. 24 (2): 359. doi:10.3390/molecules24020359. PMC 6359306. PMID 30669496.
  20. ^ Liu M, Xiao CQ, Sun MW, Tan MJ, Hu LH, Yu Q (June 2019). "Xanthatin inhibits STAT3 and NF-κB signalling by covalently binding to JAK and IKK kinases". Journal of Cellular and Molecular Medicine. 23 (6): 4301–4312. doi:10.1111/jcmm.14322. PMC 6533482. PMID 30993883.
  21. ^ Takeda S, Okajima S, Miyoshi H, Koyachi K, Matsumoto K, Shindo M, Aramaki H (2015). "(–)-Xanthatin-mediated marked up-regulation of RhoB, a sensor for damaged DNA". Fundamental Toxicological Sciences. 2 (6): 233–238. doi:10.2131/fts.2.233. ISSN 2189-115X.
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