Chemistry:Ellipticine

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Ellipticine
Ellipticine.svg
Ellipticine structure.png
Names
Preferred IUPAC name
5,11-Dimethyl-6H-pyrido[4,3-b]carbazole
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
EC Number
  • 208-264-0
KEGG
UNII
Properties
C17H14N2
Molar mass 246.313 g·mol−1
Appearance Yellow solid[1]
Density 1.257±0.06 g/cm3[2]
Melting point 316–318 °C (601–604 °F; 589–591 K)[2]
Very low[3]
Hazards
GHS pictograms GHS06: Toxic[4]
H301[4]
P264, P270, P301+310, P321, P330, P405, P501[4]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

Ellipticine is an alkaloid first extracted from trees of the species Ochrosia elliptica and Rauvolfia sandwicensis,[5][6] which inhibits the enzyme topoisomerase II via intercalative binding to DNA.[7]

Natural occurrence and synthesis

Ellipticine is an organic compound present in several trees within the genera Ochrosia, Rauvolfia, Aspidosperma, and Apocynaceae.[8] It was first isolated from Ochrosia elliptica Labill., a flowering tree native to Australia and New Caledonia which gives the alkaloid its name, in 1959,[5] and synthesised by Robert Burns Woodward later the same year.[6]

Biological activity

Ellipticine is a known intercalator, capable of entering a DNA strand between base pairs. In its intercalated state, ellipticine binds strongly[9] and lies parallel to the base pairs,[10] increasing the superhelical density of the DNA.[11] Intercalated ellipticine binds directly to topoisomerase II, an enzyme involved in DNA replication,[12] inhibiting the enzyme and resulting in powerful antitumour activity.[10] In clinical trials, ellipticine derivatives have been observed to induce remission of tumour growth, but are not used for medical purposes due to their high toxicity; side effects include nausea and vomiting, hypertension, cramp, pronounced fatigue, mouth dryness, and mycosis of the tongue and oesophagus.[13]

Further DNA damage results from the formation of covalent DNA adducts following enzymatic activation of ellipticine by with cytochromes P450 and peroxidases, meaning that ellipticine is classified as a prodrug.[14]

References

  1. ↑ Miller, R B; Dugar, S (1989). "A regiospecific total synthesis of ellipticine via nitrene insertion". Tetrahedron Letters 30 (3): 297–300. doi:10.1016/S0040-4039(00)95184-0. ISSN 0040-4039. 
  2. ↑ 2.0 2.1 "Ellipticine | 519-23-3". 2016. http://www.chemicalbook.com/ChemicalProductProperty_EN_CB6746832.htm. Retrieved 2017-05-30. 
  3. ↑ Sbai, M; Ait Lyazidi, S; Lerner, D A; del Castillo, B; Martin, M A (1996). "Use of micellar media for the fluorimetric determination of ellipticine in aqueous solutions". Journal of Pharmaceutical and Biomedical Analysis 14 (8): 959–965. doi:10.1016/S0731-7085(96)01759-1. ISSN 0731-7085. PMID 8818001. 
  4. ↑ 4.0 4.1 4.2 "Ellipticine | C17H14N2 - PubChem". 2016. https://pubchem.ncbi.nlm.nih.gov/compound/ellipticine. Retrieved 2017-05-30. 
  5. ↑ 5.0 5.1 Goodwin, S; Smith, A F; Horning, E C (1959). "Alkaloids of Ochrosia elliptica Labill.". Journal of the American Chemical Society 81 (8): 1903–1908. doi:10.1021/ja01517a031. 
  6. ↑ 6.0 6.1 Woodward, R B; Iacobucci, G A; Hochstein, I A (1959). "The synthesis of ellipticine". Journal of the American Chemical Society 81 (16): 4434–4435. doi:10.1021/ja01525a085. ISSN 0002-7863. 
  7. ↑ Auclair, C (1987). "Multimodal action of antitumor agents on DNA: The ellipticine series". Archives of Biochemistry and Biophysics 259 (1): 1–14. doi:10.1016/0003-9861(87)90463-2. ISSN 0003-9861. PMID 3318697. 
  8. ↑ Isah, T (2016). "Anticancer Alkaloids from Trees: Development into Drugs". Pharmacognosy Reviews 10 (20): 90–99. doi:10.4103/0973-7847.194047. ISSN 0973-7847. PMID 28082790. 
  9. ↑ Kohn, K W; Waring, M J; Glaubiger, D; Friedman, C A (1975). "Intercalative Binding of Ellipticine to DNA". Cancer Research 35 (1): 71–76. ISSN 0008-5472. PMID 1109798. http://cancerres.aacrjournals.org/content/35/1/71. 
  10. ↑ 10.0 10.1 Canals, A; Purciolas, M; Aymamí, J; Coll, M (2005). "The anticancer agent ellipticine unwinds DNA by intercalative binding in an orientation parallel to base pairs". Acta Crystallographica D 61 (7): 1009–1012. doi:10.1107/S0907444905015404. ISSN 0907-4449. PMID 15983425. Bibcode: 2005AcCrD..61.1009C. https://digital.csic.es/bitstream/10261/108793/1/Canals-Acta-Cryst-D-2005-v61-n7-p1009.pdf. 
  11. ↑ Chu, Y; Hsu, M T (1992). "Ellipticine increases the superhelical density of intracellular SV40 DNA by intercalation". Nucleic Acids Research 20 (15): 4033–4038. doi:10.1093/nar/20.15.4033. ISSN 0305-1048. PMID 1324474. 
  12. ↑ Froelich-Ammon, S J; Patchan, M W; Osheroff, N; Thompson, R B (1995). "Topoisomerase II binds to ellipticine in the absence or presence of DNA. Characterization of enzyme–drug interactions by fluorescence spectroscopy". Journal of Biological Chemistry 270 (25): 14998–15004. doi:10.1074/jbc.270.25.14998. ISSN 0021-9258. PMID 7797481. 
  13. ↑ Paoletti, C; Le Pecq, J B; Dat-Xuong, N; Juret, P; Garnier, H; Amiel, J L; Rouesse, J (1980). "Antitumor Activity, Pharmacology, and Toxicity of Ellipticines, Ellipticinium, and 9-Hydroxy Derivatives: Preliminary Clinical Trials of 2-Methyl-9-Hydroxy Ellipticinium (NSC 264-137)". Cancer Chemo- and Immunopharmacology. Recent Results in Cancer Research. 74. 107–123. doi:10.1007/978-3-642-81488-4_15. ISBN 978-3-642-81490-7. 
  14. ↑ Stiborová, M; Poljaková, J; Martínková, E; Ulrichová, J; Šimánek, V; Dvořák, Z; Frei, E (2012). "Ellipticine oxidation and DNA adduct formation in human hepatocytes is catalyzed by human cytochromes P450 and enhanced by cytochrome b5". Toxicology 302 (2–3): 233–241. doi:10.1016/j.tox.2012.08.004. ISSN 0300-483X. PMID 22917556. 



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