Etoposide
Synonym(s):4′-Demethylepipodophyllotoxin 9-(4,6-O-ethylidene-β-D -glucopyranoside);Etoposide;VP16;VP-16;
- CAS NO.:33419-42-0
- Empirical Formula: C29H32O13
- Molecular Weight: 588.56
- MDL number: MFCD00869325
- EINECS: 251-509-1
- SAFETY DATA SHEET (SDS)
- Update Date: 2024-11-05 21:24:55
What is Etoposide?
Absorption
Absorbed well, time to peak plasma concentration is 1-1.5 hrs. Mean bioavailability is 50% (range of 25% - 75%). Cmax and AUC values for orally administered etoposide capsules display intra- and inter-subject variability. There is no evidence of first-pass effect for etoposide.
Toxicity
Side effects include alopecia, constipation, diarrhea, nausea and vomiting and secondary malignancies (leukemia).
Description
Etoposide is a plant alkaloid and an inhibitor of topoisomerase II (IC50 = 60.3 μM). It inhibits proliferation of a variety of adenocarcinoma cells (IC50s = 0.005-12,200 μM) and human umbilical vein endothelial (HUVEC) cells (IC50 = 0.249 μM). It reduces tumor growth in an Ma human embryonal carcinoma mouse xenograft model when administered at a dose of 25 mg/kg, an effect that is enhanced by concomitant administration of the immunosuppressant cyclosporin A . Etoposide also inhibits nuclear receptor coactivator 3 (IC50 = 2.48 μM). Formulations containing etoposide have been used in combination therapy in the treatment of cancer.
Description
Etoposide is, by today’s standards, an ancient anticancer drug. In 1971, C. Keller-Juslén and co-workers at Sandoz reported its?synthesis from the natural product podophyllotoxin, a toxic lignin found in the roots and rhizomes of plants of the?Podophyllum?genus. The US Food and Drug Administration approved it for use in 1983.
Etoposide is still being used and is still being made from podophyllotoxin. But the main source, the Himalayan mayapple (Podophyllum hexandrum), is difficult to grow; so Elizabeth S. Sattely and co-workers at Stanford University sought alternative sources.
The researchers found that they could?transfer enzyme-producing genes from?P. hexandrum?to?Nicotiana benthamiana,?a wild tobacco-like plant that is easy to grow. So far, the engineered plants have produced only nanograms of etoposide aglycone, an etoposide precursor. Sattely believes that the same gene pathway can be introduced in to yeast, which reproduces prolifically and may provide greatly increased yields of the aglycone.
Chemical properties
White or almost white, crystalline powder, slightly hygroscopic
Originator
Etopos,Lemery,Mexico
The Uses of Etoposide
Etoposide is used for germinogenic tumors, ovarian, stomach, and lung cancer, Hodgkin’s disease, and non-Hodgkin’s lymphoma for both monotherapy and in combination therapy.
The Uses of Etoposide
An antitumur agent that complexes with topoisomerase II and DNA to enhance double-strand and single strand cleavage of DNA and reversible inhitit religation. Blocks the cell cycle in S-phase and G2-phase of the cell cycle. Induces apoptosis in nor
The Uses of Etoposide
A DNA topoisomerase II inhibitor. Semi-synthetic derivative of podophyllotoxin, related structurally to Teniposide. Antineoplastic.
The Uses of Etoposide
anticonvulsant
Indications
For use in combination with other chemotherapeutic agents in the treatment of refractory testicular tumors and as first line treatment in patients with small cell lung cancer. Also used to treat other malignancies such as lymphoma, non-lymphocytic leukemia, and glioblastoma multiforme.
Background
A semisynthetic derivative of podophyllotoxin that exhibits antitumor activity. Etoposide inhibits DNA synthesis by forming a complex with topoisomerase II and DNA. This complex induces breaks in double stranded DNA and prevents repair by topoisomerase II binding. Accumulated breaks in DNA prevent entry into the mitotic phase of cell division, and lead to cell death. Etoposide acts primarily in the G2 and S phases of the cell cycle.
What are the applications of Application
Etoposide (VP-16) is an apoptosis inducer that inhibits DNA synthesis via topoisomerase II inhibition.
Indications
Etoposide (VePesid) is a semisynthetic derivative of
podophyllotoxin that is produced in the roots of the
American mandrake, or May apple. Unlike podophyllotoxin
and vinca alkaloids, etoposide does not bind to microtubules.
It forms a complex with the enzyme topoisomerase
II, which results in a single-strand breakage of
DNA. It is most lethal to cells in the S- and G2-phases of
the cell cycle. Drug resistance to etoposide is thought to
be caused by decreased cellular drug accumulation.
Etoposide is most useful against testicular and ovarian
germ cell cancers, lymphomas, small cell lung cancers,
and acute myelogenous and lymphoblastic
leukemia.Toxicities include mild nausea, alopecia, allergic
reaction, phlebitis at the injection site, and bone
marrow toxicity.
Definition
ChEBI: Etoposide is a beta-D-glucoside, a furonaphthodioxole and an organic heterotetracyclic compound. It has a role as an antineoplastic agent and a DNA synthesis inhibitor. It is functionally related to a podophyllotoxin and a 4'-demethylepipodophyllotoxin.
Manufacturing Process
Preparation of 2,3-Di-O-dichloroacetyl-(4,6-O-ethylidene)-β-D-glucopyranose
(hydrogenolysis)
An over-dried 100 mL three-necked round bottom flask fitted with a stir bar,
low temperature thermometer, and H2 inlet was charged with 2,3-di-Oetoposide dichloroacetyl-1-O-benzyloxycarbonyl-(4,6-O-ethylidene)-β-D-glucopyranose
(1.8 mmol), in acetone (15-30% concentration) and 10% palladium on
activated carbon powder (0.2 mmol). The solution was stirred until uniform
and then cooled to -10°C to 0°C. After the reaction was over the catalyst was
filtered over sintered glass containing a plug of celite under reduced pressure.
The sintered glass is washed trice with one times the total reaction volume of
anhydrous acetone and the filtrates are pooled and then concentrated to
dryness under reduced pressure at a temperature close to 30°C. The crude
residue was dried under vacuum at ambient temperature and above
compound was thus obtained as white foam in 98% yield with a melting point
of 130°-132°C (from acetone).
Preparation of 4'-Demethyl-epi-podophyllotoxin-4-(2,3-di-O-dichloroacetyl-
4,6-O-ethylidene)-β-D-glucopyranoside
An oven-dried, three-neck 250 mL round bottom flask was fitted with a stir
bar, low temperature thermometer, septa and argon inlet, was introduced with
4'-demethyl-epi-podophyllotoxin (1 mmol), dry molecular sieve (1/16 δ
pellets) and anhydrous dichloromethane (20-50% concentration). 2-3-Di-Odichloroacetyl-(
4,6-O-ethylidene)-β-D-glucopyranose (1.7 mmol) in
dichloromethane (10-20% concentration) was added via double-ended needle.
The suspension was stirred until homogenous and then cooled to -40°C to -
60°C in an atmosphere of argon and in the absence of moisture. To the stirred
suspension was added via a syringe, trimethylsilyl trifluoromethane sulfonate
(2 mmol) over 30 minutes. The reaction was held at between -50°C and -
40°C for 30 minutes. The course of the coupling reaction was monitored by
thin layer chromatography. The suspension was allowed to warm to about -
30°C and filtered through a short celite/basic alumina column, eluting twice
with one times the total reaction volume of dichloromethane. The pooled
filtrate was evaporated under reduced pressure to yield the crude
intermediate product 4'-demethyl-epi-podophyllotoxin-4-(2,3-di-Odichloroacetyl-
4,6-O-ethylidene)-β-D-glucopyranose (yield 80%). This crude
product is used directly in the next step without any purification. A sample
was purified by the chromatraton for spectroscopic identification. The results
are as follows: m.p.: 242°-243°C (from methanol).
Preparation of 4-Demethyl-epi-podophyllotoxin-4-(4,6-O-ethylidene)-β-Dglucopyranose
(etoposide)
To 0.8 mmol of 4'-demethyl-epi-podophyllotoxin-4-(2,3-di-O-dichloroacetyl-
4,6-O-ethylidene)-β-D-glucopyranose in 10-25% concentration in methanol is
added 1.5 mmol of zinc acetate dihydrate. The reaction mixture is refluxed
with stirring under heating for 90 minutes. After completion of the reaction,
the mixture is cooled and the volume reduced to one third by rotary
evaporation under reduced pressure. Working up is effected by diluting the
reaction solution with 100 mL dichloromethane and 100 mL of water. The
aqueous phase was washed with 50 mL of dichloromethane. The combined
dichloromethane phases was washed twice with 50 mL water, 15 mL of
methanol was added to the first wash to prevent precipitation of etoposide.
The organic phase was dried over anhydrous sodium sulphate, filtered and
concentrated by evaporation under vacuum to an amorphous solid. This solid
was re-crystallized from methanol/n-pentane at -4°C to 0°C, thus obtaining
colorless amorphous powder of Etoposide (yield 68%), if the mother liquors
are treated the yield will be higher). Melting point: 256°-258°C.
Preparation of Etoposide employing 2,3-di-O-dichloroacetyl-(4,6-Oethylidene)-
β-D-glucopyranose and boron trifluoride etherate as catalyst
4'-Demethyl-epi-podophyllotoxin (1 mmol) and 2,3-di-O-dichloroacetyl-(4,6-
O-ethylidene)-β-D-glucopyranose (2 mmol) were introduced into dry
dichloromethane under anhydrous condition. When the temperature was
stabilized to -20°C to -30°C, boron trifluoride etherate (1.5 mmol) was added
slowly with stirring. Reaction was continued at this temperature and
monitored by thin layer chromatography. After the completion of the reaction
as evidenced by TLC, the solution was washed with water, dried over
anhydrous sodium sulfate and concentrated under reduced pressure to afford
the crude intermediate product 4'-demethyl-epi-podophyllotoxin-4-(2,3-di-Odichloroacetyl-
4,6-O-ethylidene)-β-D-glucopyranose. This crude product was
then converted to etoposide by following the procedure as above described.
The yield of final product etoposide was about 60%.
brand name
Toposar(Sicor); Vepesid (Bristol-Myers Squibb).
Therapeutic Function
Antitumor, Antineoplastic
General Description
Etoposide is available in 50- and 100-mg capsules for oral useand in 100-mg vials for IV use. The agent is approved for usein testicular cancer and small cell lung cancer. It has alsobeen used in a wide variety of cancers including NSCLC,Hodgkin’s and non-Hodgkin’s disease, Kaposi sarcoma,acute lymphocytic leukemia, neuroblastoma, choriocarcinoma,and epithelial, ovarian, testicular, gastric, endometrial,and breast cancers. Etoposide is one of the few natural productderivatives that can be administered orally. When givenby this route, bioavailability is 50%. Administration by the IVroute is also utilized, and the drug is widely distributed whengiven by either route. The agent is highly protein bound(90%) primarily to albumin. Low albumin levels may lead toan increase in free drug and require a lowering of the dose.The drug does not penetrate the blood-brain barrier at normaldoses but does during high-dose therapy. Elimination occursprimarily in the urine with 30% to 40% of an IV dose appearingas unchanged drug. The elimination half-life is 5 to 10hours. Metabolism involves opening of the lactone ring togive the hydroxy acid as the major metabolite. Epimerizationoccurs at C-3 to give the cis-lactone, which may also undergohydrolysis to give the hydroxy acid. Glucuronidation and sulfationof the 4'-OH give products that are inactive. Activemetabolites are formed as a result of CYP3A4 mediated oxidative-O-demethylation of the 3'-methoxy group to give thecatechol followed by oxidation to give the quinone. The toxicitiesof etoposide include dose-limiting myelosuppression,produces nausea and vomiting in 30% to 40% of patients,which is more commonly seen when the drug is administeredorally. The agent also produces anorexia, alopecia, mucositis,and hypersensitivity reactions that may be caused by etoposideor Cremophor EL (polyoxyethylated castor oil), which isused as a vehicle for IV administration of the drug. Leukemia,especially acute myelogenous leukemia, has been associatedwith the drugs’ ability to produce strand breaks with resultanttranslocation of genetic material. The leukemias are generallyseen 5 to 8 years posttreatment and have been associated withtranslocation of several different genes resulting in breakpointsaround the mixed lineage leukemia (MLL) gene.Transcription and translation of this altered DNA giveschimeric proteins, which form partly from the translocatedgene and partly from the MLL gene. Exactly how thesechimeric proteins lead to leukemia is not known, but similaralterations are seen with other topoisomerase inhibitors.
Biochem/physiol Actions
Etoposide is an antitumor agent that complexes with topoisomerase II and DNA to enhance double-strand and single-strand cleavage of DNA and reversibly inhibit religation. Blocks the cell cycle in in S-phase and G2-phase of the cell cycle; induces apoptosis in normal and tumor cell lines; inhibits synthesis of the oncoprotein Mdm2 and induces apoptosis in tumor lines that overexpress Mdm2.
Pharmacokinetics
Etoposide is an antineoplastic agent and an epipodophyllotoxin (a semisynthetic derivative of the podophyllotoxins). It inhibits DNA topoisomerase II, thereby ultimately inhibiting DNA synthesis. Etoposide is cell cycle dependent and phase specific, affecting mainly the S and G2 phases. Two different dose-dependent responses are seen. At high concentrations (10 μg/mL or more), lysis of cells entering mitosis is observed. At low concentrations (0.3 to 10 μg/mL), cells are inhibited from entering prophase. It does not interfere with microtubular assembly. The predominant macromolecular effect of etoposide appears to be the induction of DNA strand breaks by an interaction with DNA-topoisomerase II or the formation of free radicals.
Clinical Use
Etoposide is utilized in the treatment of small cell lung cancer and in combination with other agents in refractory testicular cancer.
Safety Profile
Poison by ingestion, intraperitoneal, intravenous, and subcutaneous routes. An experimental teratogen. Human systemic effects by ingestion and inhalation: agranulocytosis, aplastic anemia, and other changes in bone marrow. Experimental reproductive effects. Human mutation data reported. When heated to decomposition it emits acrid smoke and fumes.
Synthesis
Etoposide, [[5R-(5|á,5a|?,8a|á,9|?)]-9-[4,6-O-ethylidene-|?-D-glucopyranosyl) oxy]-] 5,8,8a,9-tetrahydro-5-(4-hydroxy-3,5-dimethoxyphenyl)furo[3,4: 6,7]-naphtho[2,3- d]-1,3-dioxol-6(5aH)-one (30.4.5), is made from 4-desmethylepipodophyllotoxin (30.4.3), the phenolic group of which being previously protected by benzyl chloroformate, which makes 4-carbobenzyloxy-4-desmethylepipodophyllotoxin (30.4.3). Next, the hydroxyl group at position C9 is esterified with 4,6-O-ethylyden-2,3-di-O-acetyl-|?-D-glucopyranose in the presence of boron trifluoride to make the corresponding glucopyranoside 30.4.4. Removing the acetyl group in the glucopyranosyl part of the molecule using zinc acetate in sodium methoxide, and also removing the benzyloxycarbonyl protection by hydrogenation using a palladium on carbon catalyst gives the desired etoposide (30.4.5).
Drug interactions
Potentially hazardous interactions with other drugs Anticoagulants: possibly enhanced anticoagulant effect with coumarins. Antipsychotics: avoid concomitant use with clozapine, increased risk of agranulocytosis. Ciclosporin: 50% reduction in etoposide clearance.
Metabolism
Primarily hepatic (through O-demethylation via the CYP450 3A4 isoenzyme pathway) with 40% excreted unchanged in the urine. Etoposide also undergoes glutathione and glucuronide conjugation which are catalyzed by GSTT1/GSTP1 and UGT1A1, respectively. Prostaglandin synthases are also responsible for the conversion of etoposide to O-demethylated metabolites (quinone).
Metabolism
The drug is more than 96% protein bound, undergoes biphasic elimination, and has a terminal half-life of 4 to 11 hours. Approximately 35 to 45% of a dose is eliminated via the kidneys, with less than 6% excreted in feces. The drug should be used with caution in patients with renal or liver disease.
storage
Store at RT
References
Hande, K. R. "Etoposide: four decades of development of a topoisomerase II inhibitor." European Journal of Cancer34.10(1998):1514.
Noda, K, et al. "Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer." New England Journal of Medicine 346.2(2002):85-91.
Properties of Etoposide
Melting point: | 236-251 °C (lit.) |
Boiling point: | 563.9°C (rough estimate) |
alpha | D20 -110.5° (c = 0.6 in chloroform) |
Density | 1.2966 (rough estimate) |
refractive index | -110.5 ° (C=0.6, CHCl3) |
storage temp. | 2-8°C |
solubility | DMSO: 30 mg/mL |
form | powder |
pka | 9.8(at 25℃) |
color | white |
Water Solubility | Insoluble in water. |
Merck | 14,3886 |
Stability: | Stable for 2 years from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 2 months |
IARC | 1 (Vol. 76, 100A) 2012, 1 (Vol. 76, 100A) 2012 |
EPA Substance Registry System | Etoposide (33419-42-0) |
Safety information for Etoposide
Signal word | Danger |
Pictogram(s) |
Exclamation Mark Irritant GHS07 Health Hazard GHS08 |
GHS Hazard Statements |
H302:Acute toxicity,oral H350:Carcinogenicity H412:Hazardous to the aquatic environment, long-term hazard |
Precautionary Statement Codes |
P201:Obtain special instructions before use. P280:Wear protective gloves/protective clothing/eye protection/face protection. P308+P313:IF exposed or concerned: Get medical advice/attention. |
Computed Descriptors for Etoposide
Abamectin manufacturer
GLP Pharma Standards
Zyphars Biopharmaceuticals Pvt. Ltd
Basil Drugs AND Pharmaceuticals Pvt Ltd
BDR Pharmaceuticals International Pvt Ltd
Mac Chem Products (India) Pvt Ltd (Naprod Group)
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