Ellipticine

Last updated
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
ECHA InfoCard 100.007.514 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 208-264-0
KEGG
PubChem CID
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 mass 246.313 g·mol−1
AppearanceYellow crystalline powder [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
Occupational safety and health (OHS/OSH):
Main hazards
toxic
GHS labelling:
GHS-pictogram-skull.svg [4]
H301 [4]
P264, P270, P301+P310, 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).

Ellipticine is a tetracyclic 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]

Contents

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]

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DNA topoisomerases are enzymes that catalyze changes in the topological state of DNA, interconverting relaxed and supercoiled forms, linked (catenated) and unlinked species, and knotted and unknotted DNA. Topological issues in DNA arise due to the intertwined nature of its double-helical structure, which, for example, can lead to overwinding of the DNA duplex during DNA replication and transcription. If left unchanged, this torsion would eventually stop the DNA or RNA polymerases involved in these processes from continuing along the DNA helix. A second topological challenge results from the linking or tangling of DNA during replication. Left unresolved, links between replicated DNA will impede cell division. The DNA topoisomerases prevent and correct these types of topological problems. They do this by binding to DNA and cutting the sugar-phosphate backbone of either one or both of the DNA strands. This transient break allows the DNA to be untangled or unwound, and, at the end of these processes, the DNA backbone is resealed. Since the overall chemical composition and connectivity of the DNA do not change, the DNA substrate and product are chemical isomers, differing only in their topology.

DNA gyrase, or simply gyrase, is an enzyme within the class of topoisomerase and is a subclass of Type II topoisomerases that reduces topological strain in an ATP dependent manner while double-stranded DNA is being unwound by elongating RNA-polymerase or by helicase in front of the progressing replication fork. It is the only known enzyme to actively contribute negative supercoiling to DNA, while it also is capable of relaxing positive supercoils. It does so by looping the template to form a crossing, then cutting one of the double helices and passing the other through it before releasing the break, changing the linking number by two in each enzymatic step. This process occurs in bacteria, whose single circular DNA is cut by DNA gyrase and the two ends are then twisted around each other to form supercoils. Gyrase is also found in eukaryotic plastids: it has been found in the apicoplast of the malarial parasite Plasmodium falciparum and in chloroplasts of several plants. Bacterial DNA gyrase is the target of many antibiotics, including nalidixic acid, novobiocin, albicidin, and ciprofloxacin.

<span class="mw-page-title-main">General transcription factor</span> Class of protein transcription factors

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<span class="mw-page-title-main">Daunorubicin</span> Chemotherapy medication

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<span class="mw-page-title-main">Anthracycline</span> Class of antibiotics

Anthracyclines are a class of drugs used in cancer chemotherapy that are extracted from Streptomyces bacterium. These compounds are used to treat many cancers, including leukemias, lymphomas, breast, stomach, uterine, ovarian, bladder cancer, and lung cancers. The first anthracycline discovered was daunorubicin, which is produced naturally by Streptomyces peucetius, a species of Actinomycetota. Clinically the most important anthracyclines are doxorubicin, daunorubicin, epirubicin and idarubicin.

<span class="mw-page-title-main">Topotecan</span> Chemical compound

Topotecan, sold under the brand name Hycamtin among others, is a chemotherapeutic agent medication that is a topoisomerase inhibitor. It is a synthetic, water-soluble analog of the natural chemical compound camptothecin. It is used in the form of its hydrochloride salt to treat ovarian cancer, lung cancer and other cancer types.

<span class="mw-page-title-main">DNA supercoil</span> Amount of twist in a particular DNA strand

DNA supercoiling refers to the amount of twist in a particular DNA strand, which determines the amount of strain on it. A given strand may be "positively supercoiled" or "negatively supercoiled". The amount of a strand's supercoiling affects a number of biological processes, such as compacting DNA and regulating access to the genetic code. Certain enzymes, such as topoisomerases, change the amount of DNA supercoiling to facilitate functions such as DNA replication and transcription. The amount of supercoiling in a given strand is described by a mathematical formula that compares it to a reference state known as "relaxed B-form" DNA.

<span class="mw-page-title-main">Aporphine</span> Chemical compound

Aporphine is an alkaloid with the chemical formula C17H17N. It is the core chemical substructure of the aporphine alkaloids, a subclass of quinoline alkaloids. It can exist in either of two enantiomeric forms, (R)-aporphine and (S)-aporphine.

Topoisomerase inhibitors are chemical compounds that block the action of topoisomerases, which are broken into two broad subtypes: type I topoisomerases (TopI) and type II topoisomerases (TopII). Topoisomerase plays important roles in cellular reproduction and DNA organization, as they mediate the cleavage of single and double stranded DNA to relax supercoils, untangle catenanes, and condense chromosomes in eukaryotic cells. Topoisomerase inhibitors influence these essential cellular processes. Some topoisomerase inhibitors prevent topoisomerases from performing DNA strand breaks while others, deemed topoisomerase poisons, associate with topoisomerase-DNA complexes and prevent the re-ligation step of the topoisomerase mechanism. These topoisomerase-DNA-inhibitor complexes are cytotoxic agents, as the un-repaired single- and double stranded DNA breaks they cause can lead to apoptosis and cell death. Because of this ability to induce apoptosis, topoisomerase inhibitors have gained interest as therapeutics against infectious and cancerous cells.

<span class="mw-page-title-main">21-Hydroxylase</span> Human enzyme that hydroxylates steroids

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<span class="mw-page-title-main">Type I topoisomerase</span> Class of enzymes

In molecular biology Type I topoisomerases are enzymes that cut one of the two strands of double-stranded DNA, relax the strand, and reanneal the strand. They are further subdivided into two structurally and mechanistically distinct topoisomerases: type IA and type IB.

<span class="mw-page-title-main">Type II topoisomerase</span>

Type II topoisomerases are topoisomerases that cut both strands of the DNA helix simultaneously in order to manage DNA tangles and supercoils. They use the hydrolysis of ATP, unlike Type I topoisomerase. In this process, these enzymes change the linking number of circular DNA by ±2. Topoisomerases are ubiquitous enzymes, found in all living organisms.

<i>Ochrosia</i> Genus of plants

Ochrosia is a genus of flowering plants, first described in 1789. It is in the family Apocynaceae, native to Southeast Asia, Australia, and various islands of the Indian and Pacific Oceans.

  1. Ochrosia ackeringae(Teijsm. & Binn.) Miq. – Indonesia, Philippines, Papuasia, Christmas Island
  2. Ochrosia acuminataTrimen ex Valeton – Sulawesi
  3. Ochrosia alyxioidesGuillaumin – Vanuatu
  4. Ochrosia apoensisElmer – Luzon, Mindanao
  5. Ochrosia balansae(Guillaumin) Baill. ex Guillaumin – New Caledonia
  6. Ochrosia basistaminaHendrian – Sulawesi
  7. Ochrosia bodenheimarumGuillaumin – Vallée de la Toutouta in New Caledonia
  8. Ochrosia borbonicaJ.F.Gmel. – Mauritius + Réunion; naturalized in Guangdong
  9. Ochrosia brevitubaBoiteau – New Caledonia
  10. Ochrosia brownii(Fosberg & Sachet) Lorence & Butaud – Nuku Hiva in Marquesas
  11. Ochrosia citrodoraK.Schum. & Lauterb. – New Guinea
  12. Ochrosia coccinea(Teijsm. & Binn.) Miq. – Maluku, Sulawesi, New Guinea, Solomon Islands; naturalized in Guangdong
  13. Ochrosia comptaK.Schum., Hōlei – Hawaii
  14. Ochrosia ellipticaLabill. – Lord Howe Island, Queensland, New Caledonia, Vanuatu, Nauru; naturalized in Guangdong + Taiwan
  15. Ochrosia fatuhivensisFosberg & Sachet – Fatu Hiva in Marquesas but extinct
  16. Ochrosia ficifolia(S.Moore) Markgr. – New Guinea
  17. Ochrosia glomerata(Blume) F.Muell. – Borneo, Sulawesi, Philippines, Maluku, New Guinea, Solomon Islands
  18. Ochrosia grandifloraBoit. – New Caledonia
  19. Ochrosia haleakalaeH.St.John, Hōlei – Maui + island of Hawaiʻi in Hawaiian Islands
  20. Ochrosia hexandraKoidz. – Kazan-retto
  21. Ochrosia inventorumL.Allorge – New Caledonia
  22. Ochrosia iwasakiana(Koidz.) Koidz. ex Masam.
  23. Ochrosia kauaiensisH.St.John, Hōlei – Kauaʻi in Hawaiian Islands
  24. †Ochrosia kilaueaensisH.St.John, Hōlei – island of Hawaiʻi in Hawaiian Islands, but extinct
  25. Ochrosia kilneriF.Muell. – Queensland
  26. Ochrosia lifuanaGuillaumin – Loyalty Islands + Isle of Pines in New Caledonia
  27. Ochrosia mariannensisA.DC. – Mariana Islands
  28. Ochrosia mianaBaill. ex Guillaumin – New Caledonia
  29. Ochrosia minima(Markgr.) Fosberg & Boiteau – Queensland, Papua New Guinea
  30. Ochrosia moorei(F.Muell.) F.Muell. ex Benth. – Queensland, New South Wales
  31. Ochrosia mulsantiiMontrouz. – New Caledonia
  32. Ochrosia nakaiana(Koidz.) Koidz. ex H.Hara – Ogasawara-shoto
  33. Ochrosia newellianaF.M.Bailey – Queensland
  34. Ochrosia novocaledonicaDäniker – New Caledonia
  35. Ochrosia oppositifolia(Lam.) K.Schum. – Seychelles, Chagos Islands, Sri Lanka, Maldive Islands, Andaman & Nicobar Islands, Thailand, Vietnam, W Malaysia, Indonesia, Papuasia, Samoa, Tonga, Tuvalu, Vanuatu, Wallis & Futuna, French Polynesia, Line Islands, Micronesia
  36. Ochrosia poweriF.M.Bailey – Queensland, New South Wales
  37. Ochrosia sciadophyllaMarkgr – Bismarck Archipelago, Solomon Islands
  38. Ochrosia sevenetiiBoiteau – New Guinea
  39. Ochrosia silvaticaDäniker – New Caledonia
  40. Ochrosia solomonensis(Merr. & L.M.Perry) Fosberg & Boiteau – Solomon Islands
  41. Ochrosia syncarpaMarkgr. – Bali, Lombok, Timor, Flores
  42. Ochrosia tahitensisLaness. ex Pichon – Tahiti
  43. Ochrosia tenimberensisMarkgr. – Tanimbar Islands
  1. Ochrosia nukuhivensisFosberg & Sachet = Rauvolfia nukuhivensis(Fosberg & Sachet) Lorence & Butaud
  2. Ochrosia sandwicensisA.DC. = Rauvolfia sandwicensisA.DC.
  3. Ochrosia tuberculata(Vahl) Pichon = Rauvolfia sandwicensisA.DC.
<span class="mw-page-title-main">Camptothecin</span> Chemical compound

Camptothecin (CPT) is a topoisomerase inhibitor. It was discovered in 1966 by M. E. Wall and M. C. Wani in systematic screening of natural products for anticancer drugs. It was isolated from the bark and stem of Camptotheca acuminata, a tree native to China used in traditional Chinese medicine. It has been used clinically in China for the treatment of gastrointestinal tumors. CPT showed anticancer activity in preliminary clinical trials, especially against breast, ovarian, colon, lung, and stomach cancers. However, it has low solubility and adverse effects have been reported when used therapeutically, so synthetic and medicinal chemists have developed numerous syntheses of camptothecin and various derivatives to increase the benefits of the chemical, with good results. Four CPT analogues have been approved and are used in cancer chemotherapy today: topotecan, irinotecan, belotecan, and trastuzumab deruxtecan. Camptothecin has also been found in other plants including Chonemorpha fragrans.

Strictosidine synthase (EC 4.3.3.2) is an enzyme in alkaloid biosynthesis that catalyses the condensation of tryptamine with secologanin to form strictosidine in a formal Pictet–Spengler reaction:

<span class="mw-page-title-main">Indolocarbazole</span> Class of chemical compounds

Indolocarbazoles (ICZs) are a class of compounds that are under current study due to their potential as anti-cancer as well as antimicrobial drugs and the prospective number of derivatives and uses found from the basic backbone alone. First isolated in 1977, a wide range of structures and derivatives have been found or developed throughout the world. Due to the extensive number of structures available, this review will focus on the more important groups here while covering their occurrence, biological activity, biosynthesis, and laboratory synthesis.

<span class="mw-page-title-main">Ajmalicine</span> Chemical compound

Ajmalicine, also known as δ-yohimbine or raubasine, is an antihypertensive drug used in the treatment of high blood pressure. It has been marketed under numerous brand names including Card-Lamuran, Circolene, Cristanyl, Duxil, Duxor, Hydroxysarpon, Iskedyl, Isosarpan, Isquebral, Lamuran, Melanex, Raunatin, Saltucin Co, Salvalion, and Sarpan. It is an alkaloid found naturally in various plants such as Rauvolfia spp., Catharanthus roseus, and Mitragyna speciosa.

<i>Rauvolfia nukuhivensis</i> Species of plant

Rauvolfia nukuhivensis is a species of plant in the family Apocynaceae. It is endemic to Nuku Hiva in the Marquesas Islands in French Polynesia.

<span class="mw-page-title-main">Reverse gyrase</span>

Reverse gyrase is a type I topoisomerase that introduces positive supercoils into DNA, contrary to the typical negative supercoils introduced by the type II topoisomerase DNA gyrase. These positive supercoils can be introduced to DNA that is either negatively supercoiled or fully relaxed. Where DNA gyrase forms a tetramer and is capable of cleaving a double-stranded region of DNA, reverse gyrase can only cleave single stranded DNA. More specifically, reverse gyrase is a member of the type IA topoisomerase class; along with the ability to relax negatively or positively supercoiled DNA, type IA enzymes also tend to have RNA-topoisomerase activities. These RNA topoisomerases help keep longer RNA strands from becoming tangled in what are referred to as "pseudoknots." Due to their ability to interact with RNA, it is thought that this is one of the most ancient class of enzymes found to date.

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. 1 2 "Ellipticine | 519-23-3". ChemicalBook. 2016. 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. 1 2 3 "Ellipticine | C17H14N2 - PubChem". PubChem. 2016. Retrieved 2017-05-30.
  5. 1 2 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. 1 2 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. 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. 1 2 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" (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. doi:10.1016/j.tox.2012.08.004. ISSN   0300-483X. PMID   22917556.
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