Etoposide CAS 33419-42-0

Introduction：Basic information about Etoposide CAS 33419-42-0, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.

Etoposide Basic information

• Product Name: Etoposide
• Synonyms: (-)-Etoposide, (5S,5aR,8aR,9R)-9-(4-hydroxy-3,5-dimethoxyphenyl)-8-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl 4,6-O-[(1R)-ethylidene]-beta-D-glucopyranoside;EtoposideETOPOSIDE CAS:33419-42-0 MES-012;BMY-40481, Etoposide 4'-Dihydrogenphosphate, VP-16-213;Etoposide , 98.0%(LC);Etoposide for system suitability;GAL4 [(1-147) + VP16 (411-490)] from Saccharomyces cerevisiae human herpesvirus 2;Etoposide, >=98%;(5R,5aR,8aR,9S)-9-[[4,6-O-(1R)-Ethylidene-β-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
• CAS: 33419-42-0
• MF: C29H32O13
• MW: 588.56
• EINECS: 251-509-1
• Product Categories: Pharmaceutical;Inhibitors;Anti-cancer&immunity;Antineoplastic;PARADIONE;API's;Heterocycles;Antitumors for Research and Experimental Use;Biochemistry;Glucose;Carbohydrates & Derivatives;Chiral Reagents;Apoptosis Inducers;Antibiotics;Signalling;Antitumour;Sugars;Apoptosis;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 33419-42-0.mol

Etoposide Chemical Properties

• Melting point: 236-251 °C (lit.)
• alpha: D20 -110.5° (c = 0.6 in chloroform)
• Boiling point: 563.9°C (rough estimate)
• 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
• biological source: synthetic
• Water Solubility: Insoluble in water.
• Merck: 14,3886
• BCS Class: 4
• 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
• InChIKey: VJJPUSNTGOMMGY-MRVIYFEKSA-N
• SMILES: COc1cc(cc(OC)c1O)[C@H]2[C@@H]3[C@H](COC3=O)[C@H](O[C@@H]4O[C@@H]5CO[C@@H](C)O[C@H]5[C@H](O)[C@H]4O)c6cc7OCOc7cc26
• IARC: 1 (Vol. 76, 100A) 2012, 1 (Vol. 76, 100A) 2012
• EPA Substance Registry System: Etoposide (33419-42-0)

Safety Information

• Hazard Codes: T,Xi
• Risk Statements: 45-22-36/37/38
• Safety Statements: 53-45-36/37-26
• RIDADR: 3249
• WGK Germany: 3
• RTECS: KC0190000
• HazardClass: 6.1(a)
• PackingGroup: II
• HS Code: 29389090
• Storage Class: 6.1C - Combustible acute toxic Cat.3 toxic compounds or compounds which causing chronic effects
• Hazard Classifications: Acute Tox. 4 Oral Carc. 1B Repr. 2
• Hazardous Substances Data: 33419-42-0(Hazardous Substances Data)
• Toxicity: LD50 oral in rabbit: 147mg/kg

Etoposide Usage And Synthesis

Pharmacological effects

The chemical name of etoposide is 9-(4, 6-O-ethylidene-β-D-glucopyranoside)-4'-demethyl-epipodophyllotoxin. It is an off-white crystalline powder and is odorless. Upon being exposed to light, heat, its color is easy to change. It is also hydroscopic. It is almost insoluble in water, slight soluble in methanol, dimethyl sulfoxide and also ethanol.
Etoposide is the newly semi-synthetic derivative of epipodophyllotoxin and belongs to mitotic inhibitors which can make the cells be stalled in the mid-mitosis stage. It is a cell cycle specific anticancer drug. This product can act on the DNA topoisomerase II (Topo II), to form a "Drug-enzyme-DNA" complex, preventing Topo II from participating in DNA repair, resulting in the stallation of DNA replication, thereby inhibiting the proliferation of tumor cell(IC 50 = 59.2 μ M). It mainly takes effects on S phase, G2 phase cells, and caused cell arrest in the G2 phase. The experimental study has found that the complex can be reversed with the elimination of drug. In that case, Top II will become free again so the damaged DNA get repair again, reducing its anti-tumor effect. Therefore, extending the treatment time can enhance the anti-tumor activity. It is mainly used for the treatment of small cell lung cancer, malignant lymphoma, malignant germ cell tumors, and leukemia and also has certain efficacy on treating neuroblastoma, rhabdomyosarcoma, ovarian cancer, non-small cell lung cancer, stomach cancer and esophageal cancer.
This product has a bioavailability of 48% (25% to 74%) after oral administration. The plasma concentration can reach peak at 0.5 to 4 hours after taking this drug. After intravenous injection of this product, the plasma concentration of this drug exhibits biphasic elimination with the half-life of α phase being (1.4 ± 0.4) h and half-life of β phase being (5.7 ± 1.8) hours. The plasma protein binding rate is 74% to 90% with the highest concentration being found in intestine, liver, and kidney while the drug concentration in the cerebrospinal liquid is only 2% to 10% of that in the blood. It is primarily subject to renal excretion with 45% being excreted in the urine at 72 hours after the administration wherein prototype accounts for two-thirds and metabolites account for 15%. 1.5% to 16% of the drug is excreted through from faeces via the bile.

Side effects

1. Over-rapid intravenous infusion rate (less than 30 minutes for the first time of administration) may cause rash, chills, fever, bronchospasm, dyspnea and other allergic reactions.
2. The drug can cause obvious myelosuppression reaction including anemia, leukopenia and thrombocytopenia. This frequently occurs in 7 to 14 days after treatment and can recover after 20 days of stopping administration. Severe neutropenia is the dose-limiting toxicity of the drug.
3. There may be loss of appetite, nausea, vomiting, stomatitis, diarrhea, abdominal pain and constipation. Liver toxicity is rare and may be accompanied with increased level of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase and bilirubin.
4. There may be occasional elevated level of blood urea nitrogen.
5. There may be dizziness, fatigue and tiredness with occasional numbness, headaches and so on; there may be heart palpitations, ECG changes, hypotension; interstitial pneumonia may also occur; hair loss is also common.

Figure 1 the structural formula of etoposide

Contraindications

1. Patients of significantly lower amount of white blood cells and platelets should be disabled.
2. Patients of heart, liver and kidney dysfunction should be disabled.
3. Pregnant women and lactating women should be disabled.
4. Patients allergic to this drug should be disabled.

Uses

It is used as anti-cancer drug mainly used for the treatment of small cell lung cancer, testicular cancer, malignant lymphoma and acute leukemia. It also has certain efficacy in treating neuroblastoma, rhabdomyosarcoma, ovarian cancer, non-small cell lung cancer, stomach cancer and breast cancer.

Usage and Dosage

1. Oral: single-administration; daily: 60~100mg /m2; continuously apply for 10 days and repeat every 3 to 4 weeks. For combination chemotherapy, apply 50 mg/m2 per day and continue to take 3 or 5 days.
2. Intravenous infusion: Use sodium chloride injection for dilute this product of required amount (this drug is instable in 5% glucose injection and can form a fine precipitate). The concentration should not be more than 0.25 mg/ml with the intravenous infusion time being not less than 30 minutes.
Solid tumors: 60~100mg/m2 per day; continue for 3 to 5 days with repeating the medication every 3 to 4 weeks.
Leukemia: 60~100mg/m2 per day; apply for 5 consecutive days; repeat the medication at certain interval according to the blood condition.
Common pediatric dose: for intravenous infusion, administer based on volume/surface area 100~150mg/m2 for continuous 3 to 4 days.

Precautions

1. This product is not suitable for intravenous injection and the intravenous infusion rate should not be too fast and should at least last for half an hour, otherwise it can easily lead to hypotension, laryngeal spasm and other allergic reactions.
2. Don’t choose chest, abdomen and intrathecal injection for administration.
3. During the medication period, the patients should be subject be regular investigation on the peripheral blood condition as well as liver and kidney function.
4. This product should be administrated immediately after dilution. If precipitate occurs, it should be strictly prohibited.
5. This product can cause reproductive toxicity and teratogenicity to animals and can be excreted through breast milk. FDA provided the pregnancy safety of this drug being classified as D class.
This information is edited by Xiongfeng Dai from Chemicalbook.

Drug Interactions

1. Because this product has significant bone marrow suppression effect and should be taken care of when be used in combination with other anticancer drugs.
2. This product can inhibit the body's immune defense mechanism, so that vaccination is not able to stimulate the body to produce antibodies.
3. Within 3 months after the end of chemotherapy, it is not recommended for applying the vaccine virus.
4. This product has a high binding rate to the plasma protein and therefore, the drug bound to plasma protein can affect the excretion of this product.

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.

Chemical Properties

White or almost white, crystalline powder, slightly hygroscopic

Originator

Etopos,Lemery,Mexico

Uses

Etoposide is used for germinogenic tumors, ovarian, stomach, and lung cancer, Hodgkin’sdisease, and non-Hodgkin’s lymphoma for both monotherapy and in combination therapy.

Uses

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

Uses

A DNA topoisomerase II inhibitor. Semi-synthetic derivative of podophyllotoxin, related structurally to Teniposide. Antineoplastic.

Uses

anticonvulsant

Indications

Etoposide (VePesid) is a semisynthetic derivative ofpodophyllotoxin that is produced in the roots of theAmerican mandrake, or May apple. Unlike podophyllotoxinand vinca alkaloids, etoposide does not bind to microtubules.It forms a complex with the enzyme topoisomeraseII, which results in a single-strand breakage ofDNA. It is most lethal to cells in the S- and G2-phases ofthe cell cycle. Drug resistance to etoposide is thought tobe caused by decreased cellular drug accumulation.
Etoposide is most useful against testicular and ovariangerm cell cancers, lymphomas, small cell lung cancers,and acute myelogenous and lymphoblasticleukemia.Toxicities include mild nausea, alopecia, allergicreaction, phlebitis at the injection site, and bonemarrow 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 onactivated carbon powder (0.2 mmol). The solution was stirred until uniformand then cooled to -10°C to 0°C. After the reaction was over the catalyst wasfiltered over sintered glass containing a plug of celite under reduced pressure.The sintered glass is washed trice with one times the total reaction volume ofanhydrous acetone and the filtrates are pooled and then concentrated todryness under reduced pressure at a temperature close to 30°C. The cruderesidue was dried under vacuum at ambient temperature and abovecompound was thus obtained as white foam in 98% yield with a melting pointof 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 stirbar, low temperature thermometer, septa and argon inlet, was introduced with4'-demethyl-epi-podophyllotoxin (1 mmol), dry molecular sieve (1/16 δpellets) and anhydrous dichloromethane (20-50% concentration). 2-3-Di-Odichloroacetyl-(4,6-O-ethylidene)-β-D-glucopyranose (1.7 mmol) indichloromethane (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 stirredsuspension 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 bythin layer chromatography. The suspension was allowed to warm to about -30°C and filtered through a short celite/basic alumina column, eluting twicewith one times the total reaction volume of dichloromethane. The pooledfiltrate was evaporated under reduced pressure to yield the crudeintermediate product 4'-demethyl-epi-podophyllotoxin-4-(2,3-di-Odichloroacetyl-4,6-O-ethylidene)-β-D-glucopyranose (yield 80%). This crudeproduct is used directly in the next step without any purification. A samplewas purified by the chromatraton for spectroscopic identification. The resultsare 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 isadded 1.5 mmol of zinc acetate dihydrate. The reaction mixture is refluxedwith stirring under heating for 90 minutes. After completion of the reaction,the mixture is cooled and the volume reduced to one third by rotaryevaporation under reduced pressure. Working up is effected by diluting thereaction solution with 100 mL dichloromethane and 100 mL of water. Theaqueous phase was washed with 50 mL of dichloromethane. The combineddichloromethane phases was washed twice with 50 mL water, 15 mL ofmethanol was added to the first wash to prevent precipitation of etoposide.The organic phase was dried over anhydrous sodium sulphate, filtered andconcentrated by evaporation under vacuum to an amorphous solid. This solidwas re-crystallized from methanol/n-pentane at -4°C to 0°C, thus obtainingcolorless amorphous powder of Etoposide (yield 68%), if the mother liquorsare 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 drydichloromethane under anhydrous condition. When the temperature wasstabilized to -20°C to -30°C, boron trifluoride etherate (1.5 mmol) was addedslowly with stirring. Reaction was continued at this temperature andmonitored by thin layer chromatography. After the completion of the reactionas evidenced by TLC, the solution was washed with water, dried overanhydrous sodium sulfate and concentrated under reduced pressure to affordthe crude intermediate product 4'-demethyl-epi-podophyllotoxin-4-(2,3-di-Odichloroacetyl-4,6-O-ethylidene)-β-D-glucopyranose. This crude product wasthen 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.

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, whichmakes 4-carbobenzyloxy-4-desmethylepipodophyllotoxin (30.4.3). Next, the hydroxylgroup at position C9 is esterified with 4,6-O-ethylyden-2,3-di-O-acetyl-|?-D-glucopyranose inthe 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 insodium methoxide, and also removing the benzyloxycarbonyl protection by hydrogenationusing 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

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

Background

An anti-tumor agent that is commonly used as an apoptosis inducer, etoposide is a topoisomerase II inhibitor with an IC50 of 59.2 µM. Etoposide stabilizes a covalent topoisomerase II-cleaved DNA intermediate complex in the catalytic cycle of the enzyme, leading to genomic instability and cell death. This mechanism of action has been shown to delay progression of the cell cycle through the late S and early G2 phase.

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.

Etoposide Preparation Products And Raw materials

• Raw materials: 4'-Demethylepipodophyllotoxin-->Boron trifluoride diethyl etherate-->Zinc acetate dihydrate-->Palladium hydroxide-->Trimethylsilyl trifluoromethanesulfonate-->Furo[3',4':6,7]naphtho[2,3-d]-1,3-dioxol-6(5aH)-one, 9-[[4,6-O-(1R)-ethylidene-2,3-bis-O-(phenylmethyl)-β-D-glucopyranosyl]oxy]-5,8,8a,9-tetrahydro-5-(4-hydroxy-3,5-dimethoxyphenyl)-, (5R,5aR,8aR,9S)--->Tetrahydrofuran-->Hydrogen
• Preparation Products: 4'-demethylepipodophyllotoxin-9 beta-glucopyranoside