Etoposide, 依托泊苷

Etoposide is a cytotoxic drug used in cancer chemotherapy. It inhibits DNA replication through inhibition of DNA topoisomerase II, thus catalysing cell cycle arrest and apoptosis. This compoud, Etoposide-d4, is a deuterated form of the drug. 

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.

Potent anti-cancer compound. Induces apoptosis in normal and tumor cell lines. DNA Topoisomerase II activity inhibitor. Increases Topo II-mediated DNA breakage primarily by inhibiting the ability of the enzyme to religate cleaved nucleic acid molecules. Does not lead to immediate block of DNS synthesis, induces a progressive inhibition of DNA replication. p53 activator. Blocks the cell cycle between the end of the S phase and the early G2 phase. Oncoprotein Mdm2 synthesis inhibitor. Apoptosis inducer through the cytochrome c/Apaf-1/caspase-9 pathway and the Fas-mediated death signaling pathway. Cell cycle checkpoint activator. Affects gene expression at different levels (chromatin remodeling, transcrip- tion and alternative splicing). Chemotherapeutic compound used in cancers. Used in conditioning regimen prior to a bone marrow or blood stem cell transplantation. Highly effective in mobilizing stem cells.

Etoposide is a semisynthetic derivative of podophyllotoxin, a substance extracted from the mandrake root Podophyllum peltatum. Possessing potent antineoplastic properties, etoposide binds to and inhibits topoisomerase II and its function in ligating cleaved DNA molecules, resulting in the accumulation of single- or double-strand DNA breaks, the inhibition of DNA replication and transcription, and apoptotic cell death. Etoposide acts primarily in the G2 and S phases of the cell cycle. (NCI04)

Etoposide, also known as toposar or vepesid, belongs to the class of organic compounds known as podophyllotoxins. These are tetralin lignans in which the benzene moiety of the tetralin skeleton is fused to a 1, 3-dioxolane and the cyclohexane is fused to a butyrolactone (pyrrolidin-2-one). Etoposide is a drug which is used 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. Etoposide exists as a solid and is considered to be practically insoluble (in water) and relatively neutral. Etoposide has been detected in multiple biofluids, such as urine and blood. Within the cell, etoposide is primarily located in the cytoplasm and membrane (predicted from logP). Etoposide participates in a number of enzymatic reactions. In particular, Etoposide can be converted into etoposide ortho-quinone through the action of the enzymes prostaglandin g/h synthase 1 and prostaglandin g/h synthase 2. In addition, Etoposide and uridine diphosphate glucuronic acid can be converted into etoposide glucuronide and uridine 5'-diphosphate; which is mediated by the enzyme UDP-glucuronosyltransferase 1-1. In humans, etoposide is involved in the etoposide metabolism pathway and the etoposide action pathway. Etoposide is formally rated as a carcinogen (by IARC 1) and is also a potentially toxic compound.

Etoposide and teniposide are semisynthetic analogues of podophyllotoxin that are used as antineoplastic agents in the therapy of several forms of solid tumors, leukemia and lymphoma, usually in combination with other agents. Both etoposide and teniposide are associated with an appreciable rate of serum enzyme elevations during therapy, and high doses have been implicated in causing clinically apparent acute liver injury including sinusoidal obstruction syndrome.

Title: Etoposide

CAS Registry Number: 33419-42-0

CAS Name: 9-[(4,6-O-Ethylidene-b-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

Additional Names: 4'-demethylepipodophyllotoxin 9-[4,6-O-ethylidene-b-D-glucopyranoside]; EPEG

Manufacturers' Codes: NSC-141540; VP-16-213

Trademarks: Lastet (Nippon Kayaku); Vepesid (BMS)

Molecular Formula: C29H32O13

Molecular Weight: 588.56

Percent Composition: C 59.18%, H 5.48%, O 35.34%

Literature References: DNA topoisomerase II inhibitor. Semi-synthetic deriv of podophyllotoxin, related structurally to teniposide, q.q.v. Prepn: C. Keller-Juslén et al., US 3524844 (1970 to Sandoz); idem et al., J. Med. Chem. 14, 936 (1971). Teratogenicity and cytogenicity study: S. M. Sieber et al., Teratology 18, 31 (1978). Review of pharmacokinetics and assay methods: P. I. Clark, M. L. Slevin, Clin. Pharmacokinet. 12, 223-252 (1987). Comprehensive description: J. J. M. Holthuis et al., Anal. Profiles Drug Subs. 18, 121-151 (1989). Review of pharmacology and clinical experience: J. D. Hainsworth, F. A. Greco, Ann. Oncol. 6, 325-341 (1995); S. Joel, Cancer Treat. Rev. 22, 179-221 (1996).

Properties: Crystals from methanol, mp 236-251°. [a]D20 -110.5° (c = 0.6 in chloroform). uv max (abs methanol): 283 nm (e 4245). pKa 9.8. Very sol in methanol, chloroform; slightly sol in ethanol; sparingly sol in water.

Melting point: mp 236-251°

pKa: pKa 9.8

Optical Rotation: [a]D20 -110.5° (c = 0.6 in chloroform)

Absorption maximum: uv max (abs methanol): 283 nm (e 4245)

Derivative Type: Phosphate

CAS Registry Number: 117091-64-2

Manufacturers' Codes: BMY-40481

Trademarks: Etopophos (BMS)

Molecular Formula: C29H33O16P

Molecular Weight: 668.54

Percent Composition: C 52.10%, H 4.98%, O 38.29%, P 4.63%

Literature References: Review: A. H. I. Witterland et al., Pharm. World Sci. 18, 163-170 (1996).

Properties: Sol in water. Practically insol in organic solvents.

Therap-Cat: Antineoplastic.

Keywords: Antineoplastic; Alkaloids/Natural Products; Podophyllum Derivatives; Topoisomerase II Inhibitor.

COA:

Product name: Etoposide                     CAS: 33419-42-0