ChemicalBook CAS DataBase List 33419-42-0

33419-42-0

Name	Etoposide
CAS	33419-42-0
EINECS(EC#)	251-509-1
Molecular Formula	C29H32O13
MDL Number	MFCD06799401
Molecular Weight	588.56
MOL File	33419-42-0.mol

Chemical Properties

Appearance	White Crystalline Powder
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.	Store at RT
solubility	DMSO: 30 mg/mL
form	powder
pka	9.8(at 25℃)
color	white
Water Solubility	Insoluble in water.
Merck	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
IARC	1 (Vol. 76, 100A) 2012, 1 (Vol. 76, 100A) 2012
EPA Substance Registry System	Furo[3',4': 6,7]naphtho[2,3-d]-1,3-dioxol-6(5aH)-one, 9-[[4,6-O-(1R)-ethylidene-. beta.-D-glucopyranosyl]oxy]-5,8,8a,9-tetrahydro-5-(4-hydroxy-3,5-dimethoxyphenyl)-, (5R,5aR,8aR,9S)-(33419-42-0)

Safety Data

Hazard Codes	T,Xi
Risk Statements	45-22-36/37/38 less more
Safety Statements	53-45-36/37-26 less more
RIDADR	3249
WGK Germany	3
RTECS	KC0190000
HazardClass	6.1(a)
PackingGroup	II
HS Code	29389000
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. less more
Hazardous Substances Data	33419-42-0(Hazardous Substances Data)
Toxicity	LD50 oral in rabbit: 147mg/kg less more

Hazard Information

Chemical Properties

White Crystalline Powder

Usage

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

Usage

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

Usage

anticonvulsant

Biological Activity

Topoisomerase II inhibitor (IC 50 = 59.2 μ M).

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 (Item No. 12088). 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.

Originator

Etopos,Lemery,Mexico

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.

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.

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.

Clinical Use

Etoposide is utilized in the treatment of small cell lung cancer and in combination with other agents in refractory testicular cancer.

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).

Synthesis_33419-42-0

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

Material Safety Data Sheet(MSDS)

Questions And Answer

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. ;

Spectrum Detail

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33419-42-0

Chemical Properties

Safety Data

Hazard Information

Chemical Properties

Usage

Usage

Usage

Biological Activity

Description

Originator

Definition

Indications

Manufacturing Process

Brand name

Therapeutic Function

General Description

Biochem/physiol Actions

Clinical Use

Synthesis

Metabolism

storage

Material Safety Data Sheet(MSDS)

Questions And Answer

Pharmacological effects

Side effects

Contraindications

Uses

Usage and Dosage

Precautions

Drug Interactions

Spectrum Detail

Supplier

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