替尼泊苷,Teniposide

Topoisomerase II inhibitor. A podophyllotoxin derivative. Induces apoptosis in vitro and in vivo.

Teniposide is a topoisomerase II poison. It promotes calf thymus topoisomerase II-mediated DNA cleavage when used at concentrations ranging from 0.04 to 40 µg/ml. Teniposide induces single- and double-stranded DNA breaks in a concentration-dependent manner. It inhibits the proliferation of A549 lung cancer cells (IC50 = 0.7 µM). Teniposide induces cell cycle arrest at the S phase and apoptosis in Tca8113 tongue squamous cell carcinoma cells when used at a concentration of 5 mg/L and induces cell cycle arrest at the G2/M phase when used at 0.15 mg/L. It reduces tumor growth and inhibits metastasis in a 3LL murine Lewis lung carcinoma model when administered at a dose of 6.5 mg/kg. Formulations containing teniposide have been used in combination therapy in the treatment of refractory childhood acute lymphoblastic leukemia.

Teniposide is a semisynthetic derivative of podophyllotoxin with antineoplastic activity. Teniposide forms a ternary complex with the enzyme topoisomerase II and DNA, resulting in dose-dependent single- and double-stranded breaks in DNA, DNA: protein cross-links, inhibition of DNA strand religation, and cytotoxicity. This agent acts in the late S or early G phase of the cell cycle. (NCI04)

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.

Teniposide, also known as VM-26 or vumon, 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). Teniposide exists as a solid and is considered to be practically insoluble (in water) and relatively neutral. Teniposide has been detected in multiple biofluids, such as urine and blood. Within the cell, teniposide is primarily located in the cytoplasm and membrane (predicted from logP). Teniposide can be converted into teniposide catechol derivative and formaldehyde through the action of the enzymes cytochrome P450 3A4 and cytochrome P450 3A5. In humans, teniposide is involved in the teniposide action pathway and the teniposide metabolism pathway. Teniposide is formally rated as a probable carcinogen (by IARC 2A) and is also a potentially toxic compound.

Title: Teniposide

CAS Registry Number: 29767-20-2

CAS Name: (5R,5aR,8aR,9S)-5,8,8a,9-Tetrahydro-5-(4-hydroxy-3,5-dimethoxyphenyl)-9-[[4,6-O-[(R)-2-thienylmethylene]-b-D-glucopyranosyl]oxy]furo[3¢,4¢:6,7]naphtho[2,3-d]-1,3-dioxol-6(5aH)-one

Additional Names: 4¢-demethylepipodophyllotoxin 9-(4,6-O-2-thenylidene-b-D-glucopyranoside); 4¢-demethylepipodophyllotoxin-b-D-thenylidine glucoside; ETP

Manufacturers' Codes: NSC-122819; VM-26

Trademarks: Vehem-Sandoz (Sandoz); Vumon (BMS)

Molecular Formula: C32H32O13S

Molecular Weight: 656.65

Percent Composition: C 58.53%, H 4.91%, O 31.67%, S 4.88%

Literature References: Semi-synthetic derivative of podophyllotoxin, q.v. Prepn: A. Von Wartburg, ZA 6607585; C. Keeler-Juslen et al., US 3524844 (1968, 1970 both to Sandoz). Mechanism of action: H. Stählen, Eur. J. Cancer 6, 303 (1970). Pharmacology: M. Hacker, D. Roberts, Cancer Res. 37, 3287 (1977); S. M. Sieber et al., Teratology 18, 31 (1978); T. J. Vietti et al., Cancer Treat. Rep. 62, 1313 (1978). Metabolism: L. Allen, Drug Metab. Rev. 8, 119 (1978); Cancer Res. 38, 2549 (1978). Clinical studies: N. M. Gadel-Mawla et al., Cancer Treat. Rep. 62, 993 (1978); R. E. Bellet et al., ibid. 445. Studies on delayed toxicity in mice after i.p. injections: M. Hacker, D. Roberts, Cancer Res. 35, 1756 (1975); H. Stählin, Eur. J. Cancer 12, 925 (1976). Review of pharmacology, pharmacokinetics and assay methods: P. I. Clark, M. L. Slevin, Clin. Pharmacokinet. 12, 223-252 (1987). Comprehensive description: J. J. Kettenes-van den Bosch et al., Anal. Profiles Drug Subs. 19, 575-600 (1990).

Properties: Crystals from abs ethanol, mp 242-246°. [a]D20 -107° (9:1 chloroform/methanol). uv max (methanol): 283 nm (E1%1cm 64.1). pKa 10.13.

Melting point: mp 242-246°

pKa: pKa 10.13

Optical Rotation: [a]D20 -107° (9:1 chloroform/methanol)

Absorption maximum: uv max (methanol): 283 nm (E1%1cm 64.1)

Therap-Cat: Antineoplastic.

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

COA:

Product name: Teniposide                               M.F.: C₃₂H₃₂O₁₃S

M.W._: 656.65                                               CAS: 29767-20-2