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Ellipticine

From Wikipedia, the free encyclopedia
Ellipticine
Names
Preferred IUPAC name
5,11-Dimethyl-6H-pyrido[4,3-b]carbazole
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
ECHA InfoCard100.007.514Edit this at Wikidata
EC Number
  • 208-264-0
KEGG
UNII
  • InChI=1S/C17H14N2/c1-10-14-9-18-8-7-12(14)11(2)17-16(10)13-5-3-4-6-15(13)19-17/h3-9,19H,1-2H3
  • CC1=C2C(=C(C3=C1C=CN=C3)C)C4=CC=CC=C4N2
Properties
C17H14N2
Molar mass246.313 g·mol−1
AppearanceYellow crystalline powder[1]
Density1.257±0.06 g/cm3[2]
Melting point316–318 °C (601–604 °F; 589–591 K)[2]
Very low[3]
Hazards
Occupational safety and health (OHS/OSH):
Main hazards
toxic
GHS labelling:
GHS06: Toxic[4]
H301[4]
P264,P270,P301+P310,P321,P330,P405,P501[4]
Except where otherwise noted, data are given for materials in theirstandard state (at 25 °C [77 °F], 100 kPa).
Chemical compound

Ellipticine is a tetracyclicalkaloid first extracted fromtrees of the speciesOchrosia elliptica andRauvolfia sandwicensis,[5][6] which inhibits the enzymetopoisomerase II viaintercalative binding toDNA.[7]

Natural occurrence and synthesis

[edit]

Ellipticine is anorganic compound present in several trees within the generaOchrosia,Rauvolfia,Aspidosperma, andApocynaceae.[8] It was first isolated fromOchrosia ellipticaLabill., a flowering tree native toAustralia andNew Caledonia which gives the alkaloid its name, in 1959,[5] and synthesised byRobert Burns Woodward later the same year.[6]

Biological activity

[edit]

Ellipticine is a knownintercalator, 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 thesuperhelical density of the DNA.[11] Intercalated ellipticine binds directly totopoisomerase II, anenzyme involved inDNA replication,[12] inhibiting the enzyme and resulting in powerful antitumour activity.[10] In clinical trials, ellipticine derivatives have been observed to induceremission oftumour growth, but are not used for medical purposes due to their hightoxicity; side effects includenausea andvomiting,hypertension,cramp, pronouncedfatigue, mouth dryness, andmycosis of the tongue andoesophagus.[13]

Further DNA damage results from the formation of covalentDNA adducts following enzymatic activation of ellipticine by withcytochromesP450 andperoxidases, meaning that ellipticine is classified as aprodrug.[14]

References

[edit]
  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. ^ab"Ellipticine | 519-23-3".ChemicalBook. 2016. Retrieved2017-05-30.
  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. ^abc"Ellipticine | C17H14N2 - PubChem".PubChem. 2016. Retrieved2017-05-30.
  5. ^abGoodwin, S; Smith, A F; Horning, E C (1959). "Alkaloids ofOchrosia elliptica Labill".Journal of the American Chemical Society.81 (8):1903–1908.Bibcode:1959JAChS..81.1903G.doi:10.1021/ja01517a031.
  6. ^abWoodward, R B; Iacobucci, G A; Hochstein, I A (1959). "The synthesis of ellipticine".Journal of the American Chemical Society.81 (16):4434–4435.Bibcode:1959JAChS..81.4434W.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.PMC 5214563.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.
  10. ^abCanals, A; Purciolas, M; Aymamí, J; Coll, M (2005)."The anticancer agent ellipticine unwinds DNA by intercalative binding in an orientation parallel to base pairs"(PDF).Acta Crystallographica D.61 (7):1009–1012.Bibcode:2005AcCrD..61.1009C.doi:10.1107/S0907444905015404.hdl:10261/108793.ISSN 0907-4449.PMID 15983425.
  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.PMC 334084.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. Vol. 74. pp. 107–123.doi:10.1007/978-3-642-81488-4_15.ISBN 978-3-642-81490-7.ISSN 0080-0015.PMID 7003658.{{cite book}}:|journal= ignored (help)
  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.Bibcode:2012Toxgy.302..233S.doi:10.1016/j.tox.2012.08.004.ISSN 0300-483X.PMID 22917556.
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