Podophyllotoxin Chemical Properties

Melting point:

183-184 °C (lit.)

alpha 

-110.7 º (c=1, CHCl3)

Boiling point:

453.31°C (rough estimate)

Density 

1.2649 (rough estimate)

refractive index 

1.4480 (estimate)

storage temp. 

2-8°C

solubility 

DMSO:15.0(Max Conc. mg/mL);36.2(Max Conc. mM)

pka

13.26±0.40(Predicted)

form 

Powder

color 

White to off-white

optical activity

[α]/D 131±2°, c = 1 in chloroform

Merck 

13,7628

BRN 

99163

Stability:

Very Hygroscopic

InChIKey

YJGVMLPVUAXIQN-XVVDYKMHSA-N

LogP

2.010

CAS DataBase Reference

518-28-5(CAS DataBase Reference)

Safety Information

Hazard Codes 

T

Risk Statements 

21-25-36/37/38-23/25-23/24/25

Safety Statements 

36/37/39-45-26

RIDADR 

UN 3462 6.1/PG 2

WGK Germany 

3

RTECS 

LV2500000

F 

1-8-10

HazardClass 

6.1(a)

PackingGroup 

II

HS Code 

29189090

Hazardous Substances Data

518-28-5(Hazardous Substances Data)

Toxicity

LD50 in rats (mg/kg): 8.7 i.v.; 15 i.p. (Phillips)

MSDS

• Language:English Provider:(5R,5aR,8aR,9R)-5,8,8a,9-Tetrahydro-9-hydroxy-5-(3,4,5-trimethoxyphenyl)-furo(3',4':6,7)naphtho[2,3-d]-1,3-dioxol-6(5aH)-one
• Language:English Provider:SigmaAldrich
• Language:English Provider:ACROS

Podophyllotoxin Usage And Synthesis

Description

Podophyllotoxin (2,3-butyl-4-aromatic naphthene) is isolated from guijiu(Podophyllum) . There are two species as the main source of podophyllotoxin, Podophyllum hexandrum Royle and Podophyllum peltatum .
Although podophyllotoxin has significant antitumor and antiviral activities, it showed several toxicity and side effects. Podophyllotoxin derivatives, etoposide (VP-16-213), Etopophos, amino sugar etoposide (NK6l1), and teniposide (VM26), have been developed as anticancer drugs. They are used to treat small cell lung cancer, testicular cancer, acute leukemia, malignant lymphoma, etc. But podophyllotoxin derivatives are not free of toxicity. Besides the narrowing of the anticancer spectrum and low water solubility, these drugs could induce severe myelosuppression, gastrointestinal side effects, etc.
Although the synthetic and biosynthetic pathways of podophyllotoxin have been elucidated, it is still the most effective, economic, and fast way to extract podophyllotoxin from the plant.

Chemical Properties

off-white fine crystalline powder

Physical properties

Appearance: white needle crystal powder. Solubility: freely soluble in chloroform, acetone, ethyl acetate, and benzene; soluble in ethanol and ethyl ether; and insoluble in water. Melting point: after drying the melting point is 183–184°C. Specific optical rotation: 132.7°C (chloroform).

History

Podophyllotoxin was first found in the Podophyllum peltatum L.?The first time to isolate podophyllotoxin from podophyllin was in 1880. In 1942, it was found that venereal warts could be effectively treated by application of podophyllin.Subsequently, podophyllotoxin was reported to inhibit the growth of the tumor through the inhibition of the microtubule formation. The chemical structure of podophyllotoxin was elucidated in 1951.
In the 1960s, two main podophyllotoxin derivatives were synthesized, etoposide and teniposide (VM-26) . In 1983, etoposide was approved by FDA.?Etoposide and teniposide are used in frontline cancer therapy against various cancer types, such as small cell lung cancer, testicular cancer, etc. In 1996, etoposide phosphate analog (Etopophos) was launched in America. Etopophos is the prodrug of etoposide and can be rapidly absorbed and completely converted to the parent compound in?vivo. In 1990, WHO recommended 0.5% podophyllotoxin as the first-line drug for the treatment of condyloma acuminatum. Podophyllotoxin creams and gels are nowadays widely used in clinical practice.

Uses

Skin treatment for genital warts caused by some types of HPVs.

Uses

antineoplastic, inhibits microtubule assembly, and human DNA topoisomerase II; antimitotic agent

Uses

Podophyllotoxin is a non-alkaloid toxin lignan extracted from the roots and rhizomes of Podophyllum species. It binds to topoisomerase II during the late S and early G2 stage, blocking tubulin polymerization and, thus, inhibiting mitosis. In addition to being used as a cathartic, purgative, antiviral agent, vesicant, and antihelminthic, podophyllotoxin is the starting material for the semi-synthesis of the anti-cancer drugs etoposide , teniposide , and etopophos.

Definition

ChEBI: An organic heterotetracyclic compound that has a furonaphthodioxole skeleton bearing a 3,4,5-trimethoxyphenyl substituent. It is found in the roots and rhizomes of Podophyllum species and is used for the topical treatment of genital warts.

Indications

Podophyllotoxin (Podofilox) is available alone and as the main cytotoxic ingredient in podophyllin (25% podophyllum resin), a mixture of toxic chemicals derived from May apple plants. The active ingredients inhibit cell mitosis. The drugs are used to treat condylomata acuminata. The most common toxic effects are skin irritation and less commonly, ulceration. Systemic absorption of podophyllin can occur (especially if applied to large, inflamed areas or mucosal surfaces), with gastrointestinal, hematological, renal, and hepatotoxic effects. In addition, seizures and peripheral neuropathy have been reported.

brand name

Condylox (Oclassen).

Biochem/physiol Actions

Inhibits microtubule assembly; antineoplastic.

Pharmacology

Antineoplastic and antiviral activities are the most pronounced pharmacological. effects of podophyllotoxin . Podophyllotoxin shows a significant inhibitory effect on the division and proliferation of epithelial cells infected by human papillomavirus (HPV), disrupts the cell cytoskeleton, and induces the necrosis and shedding of warts. It was shown that the antitumor effect of podophyllotoxin is associated with the inhibition of microtubule assembly and the induction of apoptosis. However, the antitumor effect of podophyllotoxin analogs, such as etoposide, teniposide, and Etopophos, is related to disparate mechanisms including the inhibition of DNA topoisomerase II activity and the formation of stable nucleic acid-drugenzyme complex, which induce DNA double-strand or single-strand break and eventually lead to cell death . It was also found that podophyllotoxin derivatives have immunosuppressive and anti-inflammatory effects.

Clinical Use

Podophyllotoxin is a useful agent for the treatment of condyloma acuminatum . Podophyllotoxin and its derivatives are also widely used in the treatment of cancer, such as lymphomas and lung carcinoma. Because of the several toxicity of podophyllotoxin, for example, the irritation of skin and mucous membranes, combination therapies are used to treat condyloma acuminatum or cancer.

Anticancer Research

Podophyllotoxin (PTOX) is an aryl-tetralin lignan and has been originallyisolated from Podophyllum peltatum L. (American podophyllum or Mayapple;family Podophyllaceae). Later, it is also isolated from several species like P.hexandrum Royle (Indian podophyllum) and P. pleianthum (Taiwanese podophyllum).PTOX has also been reported in other plants such as Linum spp., Callitrisspp., Juniperus spp., Thuja spp., Hyptis spp., Thymus spp., Teucrium spp., Nepetaspp., Dysosma spp., Diphylleia spp., and Jeffersoniana spp. (Ionkova 2007;Yousefzadi et al. 2010). PTOX shows strong cytotoxic activity against various cancercell lines. However, PTOX is too toxic for the treatment of neoplastic diseasesin humans; it is used as a precursor for chemical synthesis of semisynthetic antineoplasticdrugs, etoposide, Etopophos, and teniposide , which are successfullyused as antitumor agents (Holthuis 1988; Cragg and Newman 2005).Podophyllotoxin derivatives are used in the treatment of lymphomas, acute leukemia,and testicular, lung, ovarian, bladder, and brain cancer (Srivastava et al. 2005).Podophyllum spp. are the major source of PTOX, and their availability is limited innature, and some species are categorized as endangered. Moreover, the chemicalsynthesis of podophyllotoxin is an expensive process; therefore, biotechnologicalproduction of podophyllotoxin using plant cell and tissue cultures has been preferredby various research groups (Farkya et al. 2004).

Anticancer Research

Podophyllotoxin istoxic for humancells and is aprecursor ofsemisyntheticantineoplastic drugs(e.g., etoposide,etopophos, andteniposide).

Purification Methods

The toxin recrystallises form *C6H6 (with 0.5C6H6), EtOH/*C6H6, aqueous EtOH (with 1-1.5H2O, m 114-115o) and CH2Cl2/pentane. When dried at 100o/10mm it has m 183-184o. [UV: Stoll et al. Helv Chim Acta 37 1747 1954, IR: Schecler et al. J Org Chem 21 288 1956.] It is an inhibitor of microtubule assembly [Prasad et al. Biochemistry 25 739 1986]. [Beilstein 19/10 V 666.]

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