Ellipticine Explained

Ellipticine is a tetracyclic alkaloid first extracted from trees of the species Ochrosia elliptica and Rauvolfia sandwicensis,[1] [2] which inhibits the enzyme topoisomerase II via intercalative binding to DNA.[3]

Natural occurrence and synthesis

Ellipticine is an organic compound present in several trees within the genera Ochrosia, Rauvolfia, Aspidosperma, and Apocynaceae.[4] 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,[1] and synthesised by Robert Burns Woodward later the same year.[2]

Biological activity

Ellipticine is a known intercalator, capable of entering a DNA strand between base pairs. In its intercalated state, ellipticine binds strongly[5] and lies parallel to the base pairs,[6] increasing the superhelical density of the DNA.[7] Intercalated ellipticine binds directly to topoisomerase II, an enzyme involved in DNA replication,[8] inhibiting the enzyme and resulting in powerful antitumour activity.[6] 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.[9]

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.[10]

Notes and References

  1. 81 . 8 . 1903–1908 . Goodwin . S . Smith . A F . Horning . E C . Alkaloids of Ochrosia elliptica Labill. . Journal of the American Chemical Society . 1959 . 10.1021/ja01517a031 .
  2. 10.1021/ja01525a085 . 0002-7863 . 81 . 16 . 4434–4435 . Woodward . R B . Robert Burns Woodward . Iacobucci . G A . Hochstein . I A . The synthesis of ellipticine . Journal of the American Chemical Society . 1959 .
  3. 10.1016/0003-9861(87)90463-2 . 0003-9861 . 259 . 1 . 1–14 . Auclair . C . Multimodal action of antitumor agents on DNA: The ellipticine series . Archives of Biochemistry and Biophysics . 1987 . 3318697 .
  4. 10.4103/0973-7847.194047 . 0973-7847 . 10 . 20 . 90–99 . Isah . T . Anticancer Alkaloids from Trees: Development into Drugs . Pharmacognosy Reviews . 2016 . 28082790 . 5214563 . free .
  5. 0008-5472 . 35 . 1 . 71–76 . Kohn . K W . Waring . M J . Glaubiger . D . Friedman . C A . Intercalative Binding of Ellipticine to DNA . Cancer Research . 1975 . 1109798 .
  6. 10.1107/S0907444905015404 . 0907-4449 . 61 . 7 . 1009–1012 . Canals . A . Purciolas . M . Aymamí . J . Coll . M . The anticancer agent ellipticine unwinds DNA by intercalative binding in an orientation parallel to base pairs . Acta Crystallographica D . 2005 . 15983425 . 2005AcCrD..61.1009C . 10261/108793 . free .
  7. 0305-1048 . 20 . 15 . 4033–4038 . Chu . Y . Hsu . M T . Ellipticine increases the superhelical density of intracellular SV40 DNA by intercalation . Nucleic Acids Research . 1992 . 1324474 . 334084 . 10.1093/nar/20.15.4033 .
  8. 0021-9258 . 270 . 25 . 14998–15004 . Froelich-Ammon . S J . Patchan . M W . Osheroff . N . Thompson . R B . Topoisomerase II binds to ellipticine in the absence or presence of DNA. Characterization of enzyme–drug interactions by fluorescence spectroscopy . Journal of Biological Chemistry . 1995 . 7797481 . 10.1074/jbc.270.25.14998 . free .
  9. Book: 0080-0015 . 74 . 107–123 . Paoletti . C . Le Pecq . J B . Dat-Xuong . N . Juret . P . Garnier . H . Amiel . J L . Rouesse . J . Antitumor Activity, Pharmacology, and Toxicity of Ellipticines, Ellipticinium, and 9-Hydroxy Derivatives: Preliminary Clinical Trials of 2-Methyl-9-Hydroxy Ellipticinium (NSC 264-137) . Recent Results in Cancer Research . Cancer Chemo- and Immunopharmacology . Recent Results in Cancer Research. Fortschritte der Krebsforschung. Progres dans les Recherches Sur le Cancer . 1980 . 7003658 . 10.1007/978-3-642-81488-4_15 . 978-3-642-81490-7 .
  10. 10.1016/j.tox.2012.08.004 . 22917556 . 0300-483X . 302 . 2–3 . 233–241 . Stiborová . M . Poljaková . J . Martínková . E . Ulrichová . J . Šimánek . V . Dvořák . Z . Frei . E . Ellipticine oxidation and DNA adduct formation in human hepatocytes is catalyzed by human cytochromes P450 and enhanced by cytochrome b5 . Toxicology . 2012 .

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