Ellipticine

{{Chembox | ImageFile = Ellipticine.svg | ImageFile1 = Ellipticine_structure.png | PIN = 5,11-Dimethyl-6''H''-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<ref name="miller1989regiospecific"> {{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 }} </ref> | Density = 1.257±0.06 g/cm³<ref name="chemicalbook"> {{Cite web | url=http://www.chemicalbook.com/ChemicalProductProperty_EN_CB6746832.htm | title=Ellipticine {{!}} 519-23-3 | year=2016 |website=ChemicalBook | accessdate = 2017-05-30 }} </ref> | MeltingPtC = 316–318 | MeltingPt_ref = <ref name="chemicalbook"/> | BoilingPt = | Solubility = Very low<ref name="sbai1996use"> {{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 }} </ref> }} | Section3 = {{Chembox Hazards | MainHazards = toxic | FlashPt = | AutoignitionPt = | GHSPictograms = {{GHS06}}<ref name="pubchem">{{Cite web | url=https://pubchem.ncbi.nlm.nih.gov/compound/ellipticine| title=Ellipticine {{!}} C17H14N2 - PubChem | year=2016| website=PubChem| accessdate = 2017-05-30}}</ref> | HPhrases = {{H-phrases|301}}<ref name="pubchem"/> | PPhrases = {{P-phrases|264|270|301+310|321|330|405|501}}<ref name="pubchem"/> }} }}

'''Ellipticine''' is a tetracyclic alkaloid first extracted from the tree species ''Ochrosia elliptica'' and ''Rauvolfia sandwicensis''<ref name="goodwin1959alkaloids"> {{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 }} </ref><ref name="woodward1959synthesis"> {{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 }} </ref> which inhibits the enzyme topoisomerase II via intercalative binding to DNA.<ref name="auclair1987multimodal"> {{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 }} </ref>

== Natural occurrence and synthesis == Ellipticine is an organic compound present in several trees within the genera ''Ochrosia'', ''Rauvolfia'', and ''Aspidosperma''.<ref name="isah2016anticancer"> {{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 }} </ref> It was first isolated from ''Ochrosia elliptica'' <small>Labill.</small>, a flowering tree native to Australia and New Caledonia which gives the alkaloid its name, in 1959,<ref name="goodwin1959alkaloids"/> and synthesised by Robert Burns Woodward later the same year.<ref name="woodward1959synthesis"/>

thumb|Woodward's synthesis of ellipticine.|center|628x628px

== Biological activity == Ellipticine is a known intercalator, capable of entering a DNA strand between base pairs. In its intercalated state, ellipticine binds strongly<ref name="kohn1975intercalative"> {{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 }} </ref> and lies parallel to the base pairs,<ref name="canals2005anticancer"> {{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 }} </ref> increasing the superhelical density of the DNA.<ref name="chu1992ellipticine"> {{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 }} </ref> Intercalated ellipticine binds directly to topoisomerase II, an enzyme involved in DNA replication,<ref name="froelichammon1995topoisomerase"> {{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 }} </ref> inhibiting the enzyme and resulting in powerful antitumour activity.<ref name="canals2005anticancer"/> 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.<ref name="paoletti1980antitumor"> {{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 }} </ref>

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.<ref name="stiborova2012ellipticine"> {{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 }} </ref>

== References == {{reflist}}

Category:Indole alkaloids Category:Isoquinoline alkaloids Category:Carbazoles Category:Heterocyclic compounds with 4 rings Category:Nitrogen heterocycles Category:DNA replication inhibitors Category:Prodrugs Category:Topoisomerase inhibitors Category:DNA intercalaters Category:Plant toxins