ellipticine
{{Chembox
| ImageFile = Ellipticine.svg
| ImageFile1 = Ellipticine_structure.png
| PIN = 5,11-Dimethyl-6H-pyrido[4,3-b]carbazole
| OtherNames =
| Section1 = {{Chembox Identifiers
| CASNo = 519-23-3
| PubChem = 3213
| SMILES = CC1=C2C(=C(C3=C1C=CN=C3)C)C4=CC=CC=C4N2
| EC_number = 208-264-0
| 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
| UNII = 117VLW7484
| ChemSpiderID = 3100
| ChEBI = 4776
| KEGG = C09154
}}
| Section2 = {{Chembox Properties
| C = 17
| H = 14
| N = 2
| Appearance = Yellow crystalline powder
{{Cite journal
| doi = 10.1016/S0040-4039(00)95184-0
| issn = 0040-4039
| volume = 30
| issue = 3
| pages = 297–300
| last1 = Miller
| first1 = R B
| last2 = Dugar
| first2 = S
| title = A regiospecific total synthesis of ellipticine via nitrene insertion
| journal = Tetrahedron Letters
| date = 1989
}}
{{Cite web
| url=http://www.chemicalbook.com/ChemicalProductProperty_EN_CB6746832.htm
| title=Ellipticine {{!}} 519-23-3
| year=2016
|website=ChemicalBook
| accessdate = 2017-05-30
}}
| MeltingPtC = 316–318
| BoilingPt =
{{Cite journal
| doi = 10.1016/S0731-7085(96)01759-1
| issn = 0731-7085
| volume = 14
| issue = 8
| pages = 959–965
| last1 = Sbai
| first1 = M
| last2 = Ait Lyazidi
| first2 = S
| last3 = Lerner
| first3 = D A
| last4 = del Castillo
| first4 = B
| last5 = Martin
| first5 = M A
| title = Use of micellar media for the fluorimetric determination of ellipticine in aqueous solutions
| journal = Journal of Pharmaceutical and Biomedical Analysis
| date = 1996
| pmid = 8818001
}}
}}
| Section3 = {{Chembox Hazards
| MainHazards = toxic
| FlashPt =
| AutoignitionPt =
| GHSPictograms = {{GHS06}}{{Cite web | url=https://pubchem.ncbi.nlm.nih.gov/compound/ellipticine| title=Ellipticine {{!}} C17H14N2 - PubChem | year=2016| website=PubChem| accessdate = 2017-05-30}}
| HPhrases = {{H-phrases|301}}
| PPhrases = {{P-phrases|264|270|301+310|321|330|405|501}}
}}
}}
Ellipticine is a tetracyclic alkaloid first extracted from the tree species Ochrosia elliptica and Rauvolfia sandwicensis
{{Cite journal
| volume = 81
| issue = 8
| pages = 1903–1908
| last1 = Goodwin
| first1 = S
| last2 = Smith
| first2 = A F
| last3 = Horning
| first3 = E C
| title = Alkaloids of Ochrosia elliptica Labill.
| journal = Journal of the American Chemical Society
| date = 1959
| doi = 10.1021/ja01517a031
| bibcode = 1959JAChS..81.1903G
}}
{{Cite journal
| doi = 10.1021/ja01525a085
| issn = 0002-7863
| volume = 81
| issue = 16
| pages = 4434–4435
| last1 = Woodward
| first1 = R B
| author1-link = Robert Burns Woodward
| last2 = Iacobucci
| first2 = G A
| last3 = Hochstein
| first3 = I A
| title = The synthesis of ellipticine
| journal = Journal of the American Chemical Society
| date = 1959
| bibcode = 1959JAChS..81.4434W
}}
which inhibits the enzyme topoisomerase II via intercalative binding to DNA.
{{Cite journal
| doi = 10.1016/0003-9861(87)90463-2
| issn = 0003-9861
| volume = 259
| issue = 1
| pages = 1–14
| last = Auclair
| first = C
| title = Multimodal action of antitumor agents on DNA: The ellipticine series
| journal = Archives of Biochemistry and Biophysics
| date = 1987
| pmid = 3318697
}}
Natural occurrence and synthesis
Ellipticine is an organic compound present in several trees within the genera Ochrosia, Rauvolfia, and Aspidosperma.
{{Cite journal
| doi = 10.4103/0973-7847.194047
| issn = 0973-7847
| volume = 10
| issue = 20
| pages = 90–99
| last = Isah
| first = T
| title = Anticancer Alkaloids from Trees: Development into Drugs
| journal = Pharmacognosy Reviews
| date = 2016
| pmid = 28082790
| pmc = 5214563
| doi-access = free
}}
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, and synthesised by Robert Burns Woodward later the same year.
Biological activity
Ellipticine is a known intercalator, capable of entering a DNA strand between base pairs. In its intercalated state, ellipticine binds strongly
{{Cite journal
| issn = 0008-5472
| volume = 35
| issue = 1
| pages = 71–76
| last1 = Kohn
| first1 = K W
| last2 = Waring
| first2 = M J
| last3 = Glaubiger
| first3 = D
| last4 = Friedman
| first4 = C A
| title = Intercalative Binding of Ellipticine to DNA
| journal = Cancer Research
| date = 1975
| url = http://cancerres.aacrjournals.org/content/35/1/71
| pmid = 1109798
}}
and lies parallel to the base pairs,
{{Cite journal
| doi = 10.1107/S0907444905015404
| issn = 0907-4449
| volume = 61
| issue = 7
| pages = 1009–1012
| last1 = Canals
| first1 = A
| last2 = Purciolas
| first2 = M
| last3 = Aymamí
| first3 = J
| last4 = Coll
| first4 = M
| title = The anticancer agent ellipticine unwinds DNA by intercalative binding in an orientation parallel to base pairs
| journal = Acta Crystallographica D
| date = 2005
| pmid = 15983425
| bibcode = 2005AcCrD..61.1009C
| hdl = 10261/108793
| url = https://digital.csic.es/bitstream/10261/108793/1/Canals-Acta-Cryst-D-2005-v61-n7-p1009.pdf
| hdl-access = free
}}
increasing the superhelical density of the DNA.
{{Cite journal
| issn = 0305-1048
| volume = 20
| issue = 15
| pages = 4033–4038
| last1 = Chu
| first1 = Y
| last2 = Hsu
| first2 = M T
| title = Ellipticine increases the superhelical density of intracellular SV40 DNA by intercalation
| journal = Nucleic Acids Research
| date = 1992
| pmid = 1324474
| pmc = 334084
| doi = 10.1093/nar/20.15.4033
}}
Intercalated ellipticine binds directly to topoisomerase II, an enzyme involved in DNA replication,
{{Cite journal
| issn = 0021-9258
| volume = 270
| issue = 25
| pages = 14998–15004
| last1 = Froelich-Ammon
| first1 = S J
| last2 = Patchan
| first2 = M W
| last3 = Osheroff
| first3 = N
| last4 = Thompson
| first4 = R B
| title = Topoisomerase II binds to ellipticine in the absence or presence of DNA. Characterization of enzyme–drug interactions by fluorescence spectroscopy
| journal = Journal of Biological Chemistry
| date = 1995
| pmid = 7797481
| doi = 10.1074/jbc.270.25.14998
| doi-access = free
}}
inhibiting the enzyme and resulting in powerful antitumour activity. 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.
{{Cite book
| issn = 0080-0015
| volume = 74
| pages = 107–123
| last1 = Paoletti
| first1 = C
| last2 = Le Pecq
| first2 = J B
| last3 = Dat-Xuong
| first3 = N
| last4 = Juret
| first4 = P
| last5 = Garnier
| first5 = H
| last6 = Amiel
| first6 = J L
| last7 = Rouesse
| first7 = J
| chapter = Antitumor Activity, Pharmacology, and Toxicity of Ellipticines, Ellipticinium, and 9-Hydroxy Derivatives: Preliminary Clinical Trials of 2-Methyl-9-Hydroxy Ellipticinium (NSC 264-137)
| series = Recent Results in Cancer Research
| title = Cancer Chemo- and Immunopharmacology
| journal = Recent Results in Cancer Research. Fortschritte der Krebsforschung. Progres dans les Recherches Sur le Cancer
| date = 1980
| pmid = 7003658
| doi = 10.1007/978-3-642-81488-4_15
| isbn = 978-3-642-81490-7
}}
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.
{{Cite journal
| doi = 10.1016/j.tox.2012.08.004
| pmid = 22917556
| issn = 0300-483X
| volume = 302
| issue = 2–3
| pages = 233–241
| last1 = Stiborová
| first1 = M
| last2 = Poljaková
| first2 = J
| last3 = Martínková
| first3 = E
| last4 = Ulrichová
| first4 = J
| last5 = Šimánek
| first5 = V
| last6 = Dvořák
| first6 = Z
| last7 = Frei
| first7 = E
| title = Ellipticine oxidation and DNA adduct formation in human hepatocytes is catalyzed by human cytochromes P450 and enhanced by cytochrome b5
| journal = Toxicology
| date = 2012
| bibcode = 2012Toxgy.302..233S
}}