U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

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
Structure of ELLIPTICINE

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

HIDE SMILES / InChI

Description

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

Targets

Primary TargetPharmacologyConditionPotency
3300.0 nM [IC50]
200.0 nM [IC50]

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Unknown

Cmax

ValueDoseCo-administeredAnalytePopulation
1.75 μg/mL
20 mg/kg single, intravenous
ELLIPTICINE plasma
Rattus norvegicus

AUC

ValueDoseCo-administeredAnalytePopulation
12.29 μg × h/mL
20 mg/kg single, intravenous
ELLIPTICINE plasma
Rattus norvegicus

T1/2

ValueDoseCo-administeredAnalytePopulation
4.75 h
20 mg/kg single, intravenous
ELLIPTICINE plasma
Rattus norvegicus

Doses

AEs

PubMed

Sample Use Guides

In Vivo Use Guide
80 mg/m2 daily for 3 consecutive days every 21 days.
Route of Administration: Intravenous
In Vitro Use Guide
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.