Details
| Stereochemistry | ACHIRAL |
| Molecular Formula | C17H14N2 |
| Molecular Weight | 246.3065 |
| Optical Activity | NONE |
| Defined Stereocenters | 0 / 0 |
| E/Z Centers | 0 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
CC1=C2C=CN=CC2=C(C)C3=C1NC4=C3C=CC=C4
InChI
InChIKey=CTSPAMFJBXKSOY-UHFFFAOYSA-N
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
DescriptionCurator's Comment: The description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/16190746 | https://www.ncbi.nlm.nih.gov/pubmed/26599533 | https://www.ncbi.nlm.nih.gov/pubmed/18077363 | https://www.ncbi.nlm.nih.gov/pubmed/16936898 | https://www.ncbi.nlm.nih.gov/pubmed/8484977
Curator's Comment: The description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/16190746 | https://www.ncbi.nlm.nih.gov/pubmed/26599533 | https://www.ncbi.nlm.nih.gov/pubmed/18077363 | https://www.ncbi.nlm.nih.gov/pubmed/16936898 | https://www.ncbi.nlm.nih.gov/pubmed/8484977
Ellipticine (5,11-dimethyl-6H-pyrido[4,3-b]carbazole), an alkaloid isolated from Apocyanaceae plants (i.e. Ochrosia borbonica, Excavatia coccinea), and several its derivatives exhibit significant antitumor and anti-HIV activities. This compound is one of the simplest naturally occurring alkaloids, having a planar structure. It was first isolated in 1959 from the leaves of the evergreen tree Ochrosia elliptica, which grows wild in Oceania. Ellipticine and its more soluble derivatives (9-hydroxyellipticine, 9-hydroxy-N2-methylellipticinium, 9-chloro-N2 -methylellipticinium and 9-methoxy-N2 -methylellipticinium) exhibit promising results for the treatment of osteolytic breast cancer metastases, kidney cancer, brain tumors and acute myeloblastic leukemia. The main reason for the interest in ellipticine and its derivatives for clinical purposes is their high efficiencies against several types of cancer, their rather limited toxic side effects and their complete lack of hematological toxicity. Nevertheless, the mutagenicity of ellipticines should be evaluated as a potential risk factor for these anticancer agents. Most ellipticines are mutagenic to Salmonella typhimurium Ames tester strains, bacteriophage T4, Neurospora crassa, and mammalian cells and induce prophage lambda in Escherichia coli. The anti-tumor therapeutic ellipticine and its derivatives act as potent anticancer agents via a combined mechanism involving cell cycle arrest and induction of apoptosis. Cell death induced by ellipticine has been shown to engage a p53-dependent pathway, cell cycle arrest, interaction with several kinases and induction of the mitochondrial pathway of apoptotic cell death. Cell cycle arrest was shown to result from DNA damage caused by a variety of tumor chemotherapeutic agents; this is also the case for ellipticines. The prevalent DNA-mediated mechanisms of anti-tumor, mutagenic and cytotoxic activities of ellipticine are (i) intercalation into DNA, (ii) inhibition of DNA topoisomerase II activity, and (iii) covalent binding to DNA in vitro and in vivo after enzymatic activation by cytochrome P450 and/or peroxidase enzymes The mechanism leading to apoptosis by ellipticine is thought to also be associated with DNA damage, by inhibition of topoisomerase II and the covalent modification of DNA. In addition, the formation of ellipticine-DNA adducts ultimately can mutate cancer cells or initiate cell death.
Originator
Approval Year
Cmax
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
1.75 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22952737 |
20 mg/kg single, intravenous dose: 20 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered: |
ELLIPTICINE plasma | Rattus norvegicus population: HEALTHY age: ADULT sex: MALE food status: FASTED |
AUC
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
12.29 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22952737 |
20 mg/kg single, intravenous dose: 20 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered: |
ELLIPTICINE plasma | Rattus norvegicus population: HEALTHY age: ADULT sex: MALE food status: FASTED |
T1/2
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
4.75 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22952737 |
20 mg/kg single, intravenous dose: 20 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered: |
ELLIPTICINE plasma | Rattus norvegicus population: HEALTHY age: ADULT sex: MALE food status: FASTED |
Doses
| Dose | Population | Adverse events |
|---|---|---|
80 mg/m2 1 times / day multiple, intravenous (unknown) Studied dose Dose: 80 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 80 mg/m2, 1 times / day Sources: |
unhealthy n = 80 Health Status: unhealthy Condition: breast cancer Sex: F Food Status: UNKNOWN Population Size: 80 Sources: |
Other AEs: Blood creatinine increased, Xerostomia... Other AEs: Blood creatinine increased (grade 1, 2 patients) Sources: Xerostomia (grade 2-3, 1%) Leukopenia (grade 2, 4 patients) Phlebitis (grade 2, 1%) Muscular cramps (grade 3, 4%) Anorexia (grade 2-3, 5%) Vomiting (grade 3, 4%) Fatigue (grade 2-3, 8%) Drug fever (grade 2, 1%) |
AEs
| AE | Significance | Dose | Population |
|---|---|---|---|
| Blood creatinine increased | grade 1, 2 patients | 80 mg/m2 1 times / day multiple, intravenous (unknown) Studied dose Dose: 80 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 80 mg/m2, 1 times / day Sources: |
unhealthy n = 80 Health Status: unhealthy Condition: breast cancer Sex: F Food Status: UNKNOWN Population Size: 80 Sources: |
| Drug fever | grade 2, 1% | 80 mg/m2 1 times / day multiple, intravenous (unknown) Studied dose Dose: 80 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 80 mg/m2, 1 times / day Sources: |
unhealthy n = 80 Health Status: unhealthy Condition: breast cancer Sex: F Food Status: UNKNOWN Population Size: 80 Sources: |
| Phlebitis | grade 2, 1% | 80 mg/m2 1 times / day multiple, intravenous (unknown) Studied dose Dose: 80 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 80 mg/m2, 1 times / day Sources: |
unhealthy n = 80 Health Status: unhealthy Condition: breast cancer Sex: F Food Status: UNKNOWN Population Size: 80 Sources: |
| Leukopenia | grade 2, 4 patients | 80 mg/m2 1 times / day multiple, intravenous (unknown) Studied dose Dose: 80 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 80 mg/m2, 1 times / day Sources: |
unhealthy n = 80 Health Status: unhealthy Condition: breast cancer Sex: F Food Status: UNKNOWN Population Size: 80 Sources: |
| Xerostomia | grade 2-3, 1% | 80 mg/m2 1 times / day multiple, intravenous (unknown) Studied dose Dose: 80 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 80 mg/m2, 1 times / day Sources: |
unhealthy n = 80 Health Status: unhealthy Condition: breast cancer Sex: F Food Status: UNKNOWN Population Size: 80 Sources: |
| Anorexia | grade 2-3, 5% | 80 mg/m2 1 times / day multiple, intravenous (unknown) Studied dose Dose: 80 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 80 mg/m2, 1 times / day Sources: |
unhealthy n = 80 Health Status: unhealthy Condition: breast cancer Sex: F Food Status: UNKNOWN Population Size: 80 Sources: |
| Fatigue | grade 2-3, 8% | 80 mg/m2 1 times / day multiple, intravenous (unknown) Studied dose Dose: 80 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 80 mg/m2, 1 times / day Sources: |
unhealthy n = 80 Health Status: unhealthy Condition: breast cancer Sex: F Food Status: UNKNOWN Population Size: 80 Sources: |
| Muscular cramps | grade 3, 4% | 80 mg/m2 1 times / day multiple, intravenous (unknown) Studied dose Dose: 80 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 80 mg/m2, 1 times / day Sources: |
unhealthy n = 80 Health Status: unhealthy Condition: breast cancer Sex: F Food Status: UNKNOWN Population Size: 80 Sources: |
| Vomiting | grade 3, 4% | 80 mg/m2 1 times / day multiple, intravenous (unknown) Studied dose Dose: 80 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 80 mg/m2, 1 times / day Sources: |
unhealthy n = 80 Health Status: unhealthy Condition: breast cancer Sex: F Food Status: UNKNOWN Population Size: 80 Sources: |
PubMed
| Title | Date | PubMed |
|---|---|---|
| The anticancer drug ellipticine forms covalent DNA adducts, mediated by human cytochromes P450, through metabolism to 13-hydroxyellipticine and ellipticine N2-oxide. | 2004 Nov 15 |
|
| Correlating gene expression with chemical scaffolds of cytotoxic agents: ellipticines as substrates and inhibitors of MDR1. | 2005 |
|
| Development of a novel cytochrome p450 bioaffinity detection system coupled online to gradient reversed-phase high-performance liquid chromatography. | 2005 Aug |
|
| The anti-proliferative inhibition of ellipticine in human breast mda-mb-231 cancer cells is through cell cycle arrest and apoptosis induction. | 2005 Aug |
|
| Oxidation of an antitumor drug ellipticine by peroxidases. | 2005 Dec |
|
| Antitumor drug ellipticine inhibits the activities of rat hepatic cytochromes P450. | 2005 Dec |
|
| Synthesis and preliminary antiproliferative evaluation of 1,3,9-triazacyclopenta[b]fluorene derivatives. | 2005 Dec |
|
| Type II topoisomerase activities in both the G1 and G2/M phases of the dinoflagellate cell cycle. | 2005 Dec |
|
| Lack of CYP1A1 expression is involved in unresponsiveness of the human hepatoma cell line SK-HEP-1 to dioxin. | 2005 Dec 30 |
|
| Synthesis of ellipticine: a radical cascade protocol to aryl- and heteroaryl-annulated[b]carbazoles. | 2005 Dec 9 |
|
| The anticancer agent ellipticine unwinds DNA by intercalative binding in an orientation parallel to base pairs. | 2005 Jul |
|
| The role of hydrogen bond acceptor groups in the interaction of substrates with Pdr5p, a major yeast drug transporter. | 2005 Jul 19 |
|
| The mechanism of ellipticine-induced apoptosis and cell cycle arrest in human breast MCF-7 cancer cells. | 2005 Jun 8 |
|
| Influence of serum protein on polycarbonate-based copolymer micelles as a delivery system for a hydrophobic anti-cancer agent. | 2005 Mar 21 |
|
| Regioselective intramolecular reactions of 2-indolylacyl radicals with pyridines: a direct synthetic entry to ellipticine quinones. | 2005 Oct 28 |
|
| Molecular modeling of wild-type and D816V c-Kit inhibition based on ATP-competitive binding of ellipticine derivatives to tyrosine kinases. | 2005 Oct 6 |
|
| Ellipticine induces apoptosis through p53-dependent pathway in human hepatocellular carcinoma HepG2 cells. | 2006 Apr 25 |
|
| Cytochromes P450 reconstituted with NADPH: P450 reductase mimic the activating and detoxicating metabolism of the anticancer drug ellipticine in microsomes. | 2006 Dec |
|
| Thermotropic phase behavior of DPPC liposome systems in the presence of the anti-cancer agent 'Ellipticine'. | 2006 Dec |
|
| Mutation P732L in human DNA topoisomerase IIbeta abolishes DNA cleavage in the presence of calcium and confers drug resistance. | 2006 Jan |
|
| Molecular mechanisms of antineoplastic action of an anticancer drug ellipticine. | 2006 Jul |
|
| Cytotoxic prenylated xanthones from the young fruit of Garcinia mangostana. | 2006 Mar |
|
| Lipid model membranes for drug interaction study. | 2006 May |
|
| Detection of a new N-oxidized metabolite of flutamide, N-[4-nitro-3-(trifluoromethyl)phenyl]hydroxylamine, in human liver microsomes and urine of prostate cancer patients. | 2006 May |
|
| Chemical transformations of oxyresveratrol (trans-2,4,3',5'-tetrahydroxystilbene) into a potent tyrosinase inhibitor and a strong cytotoxic agent. | 2006 Nov 1 |
|
| 2,4-Diamino-9H-pyrimido[4,5-b]indol-5-ols: synthesis, in vitro cytotoxic activity, and QSAR investigations. | 2006 Nov 1 |
|
| Solvent effect on the photophysical properties of the anticancer agent ellipticine. | 2006 Oct 12 |
|
| Oxidation pattern of the anticancer drug ellipticine by hepatic microsomes - similarity between human and rat systems. | 2006 Sep |
|
| Does topoisomerase II specifically recognize and cleave hairpins, cruciforms and crossovers of DNA? | 2007 Apr |
|
| Formation of colloidal suspension of hydrophobic compounds with an amphiphilic self-assembling peptide. | 2007 Apr 1 |
|
| Synthesis and biological activity of 5-aza-ellipticine derivatives. | 2007 Apr 15 |
|
| Synthesis of 6-chloroisoquinoline-5,8-diones and pyrido[3,4-b]phenazine-5,12-diones and evaluation of their cytotoxicity and DNA topoisomerase II inhibitory activity. | 2007 Jan 1 |
|
| Mammalian peroxidases activate anticancer drug ellipticine to intermediates forming deoxyguanosine adducts in DNA identical to those found in vivo and generated from 12-hydroxyellipticine and 13-hydroxyellipticine. | 2007 Jan 15 |
|
| 8-Methyl-4-(3-diethylaminopropylamino) pyrimido [4',5';4,5] thieno (2,3-b) quinoline (MDPTQ), a quinoline derivate that causes ROS-mediated apoptosis in leukemia cell lines. | 2007 Jul 1 |
|
| Formation and persistence of DNA adducts of anticancer drug ellipticine in rats. | 2007 Jul 1 |
|
| DNA adduct formation by the anticancer drug ellipticine in human leukemia HL-60 and CCRF-CEM cells. | 2007 Jul 18 |
|
| Density-functional, density-functional tight-binding, and wave function calculations on biomolecular systems. | 2007 Jul 5 |
|
| In vitro inhibition of Plasmodium falciparum by substances isolated from Amazonian antimalarial plants. | 2007 Jun |
|
| Effect of a single nucleotide polymorphism in the murine double minute 2 promoter (SNP309) on the sensitivity to topoisomerase II-targeting drugs. | 2007 Jun 15 |
|
| Abundance of aryl hydrocarbon receptor potentiates benzo[a]pyrene-induced apoptosis in Hepa1c1c7 cells via CYP1A1 activation. | 2007 Jun 3 |
|
| Synthesis and in vitro cytotoxicity evaluation of novel naphthindolizinedione derivatives. | 2007 Mar |
|
| p27 degradation by an ellipticinium series of compound via ubiquitin-proteasome pathway. | 2007 Mar |
|
| Pattern recognition methods investigation of ellipticines structure-activity relationships. | 2007 Mar |
|
| Polychlorinated biphenyls 105 and 118 form thyroid hormone receptor agonists after cytochrome P4501A1 activation in rat pituitary GH3 cells. | 2007 Nov |
|
| The anticancer drug ellipticine is a potent inducer of rat cytochromes P450 1A1 and 1A2, thereby modulating its own metabolism. | 2007 Oct |
|
| Synthesis and biological evaluation of indoloquinolines and pyridocarbazoles: a new example of unexpected photoreduction accompanying photocyclization. | 2007 Sep |
|
| Preparation of polyfunctional aryl azides from aryl triazenes. A new synthesis of ellipticine, 9-methoxyellipticine, isoellipticine, and 7-carbethoxyisoellipticine. | 2007 Sep 14 |
|
| Apoptotic epidermal growth factor (EGF)-conjugated block copolymer micelles as a nanotechnology platform for targeted combination therapy. | 2007 Sep-Oct |
|
| Role of hepatic cytochromes P450 in bioactivation of the anticancer drug ellipticine: studies with the hepatic NADPH:cytochrome P450 reductase null mouse. | 2008 Feb 1 |
|
| Neuronal activity enhances aryl hydrocarbon receptor-mediated gene expression and dioxin neurotoxicity in cortical neurons. | 2008 Mar |
Sample Use Guides
80 mg/m2 daily for 3 consecutive days every 21 days.
Route of Administration:
Intravenous
The human breast cancer cell line MCF7 and SUM159 were used for activity evaluation. The cytotoxicity of ellipticine and paclitaxel was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test. Both MCF7 and SUM159 cells present in their exponential growth phase were seeded at 1×10^4 cells/well in a 96-well plate. For a dose–response curve, DMSO stock solutions of ellipticine (10 mM) and paclitaxel (10 μM) were dissolved in culture medium to get the final concentrations of 0.5–8 μM for ellipticine and 0.5–8 nM for paclitaxel. The cells of both cell lines were replenished with fresh media containing varying concentrations of both drugs on the next day and incubated for 48 h at 37 °C in 5 % CO2-saturated atmosphere. Wells containing only the cells and medium with no drug added were taken as controls. After incubation, the cells were fed with 200 μl of fresh medium, 50 μl of MTT (Sigma-Aldrich, St. Louis, MO, USA) solution (2 mg/ml phosphate-buffered saline [PBS]) was added, and the plates were incubated for 3 h. After incubation, the media containingMTT solution was removed and the formazan crystals were dissolved by adding 200 μl of DMSO to each well. The absorbance was read at 570 nm for each well immediately using a multiwell spectrophotometer.
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71795
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DTXSID30199855
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Ellipticine
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519-23-3
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208-264-0
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m4873
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SUB33419
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4776
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100000125919
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3213
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C034192
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117VLW7484
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ACTIVE MOIETY
SALT/SOLVATE (PARENT)
