518-28-5 Usage
Description
(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, also known as Podophyllotoxin, is an organic heterotetracyclic compound derived from the roots and rhizomes of Podophyllum species. It features a furonaphthodioxole skeleton with a 3,4,5-trimethoxyphenyl substituent and exhibits significant antitumor and antiviral activities. However, it also presents several toxicity and side effects.
Uses
Used in Pharmaceutical Industry:
(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 is used as an antineoplastic agent for inhibiting microtubule assembly and human DNA topoisomerase II, acting as an antimitotic agent.
Used in Dermatology:
(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 is used as a topical treatment for genital warts caused by some types of HPVs, under the brand name Condylox (Oclassen).
Used in Anticancer Applications:
Podophyllotoxin and its derivatives, such as etoposide (VP-16-213), Etopophos, amino sugar etoposide (NK6l1), and teniposide (VM26), are used to treat various types of cancer, including small cell lung cancer, testicular cancer, acute leukemia, and malignant lymphoma. These derivatives help in narrowing the anticancer spectrum and improving the water solubility of the compound, but they are not free of toxicity and can induce severe myelosuppression and gastrointestinal side effects.
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.
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.
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.]
Check Digit Verification of cas no
The CAS Registry Mumber 518-28-5 includes 6 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 3 digits, 5,1 and 8 respectively; the second part has 2 digits, 2 and 8 respectively.
Calculate Digit Verification of CAS Registry Number 518-28:
(5*5)+(4*1)+(3*8)+(2*2)+(1*8)=65
65 % 10 = 5
So 518-28-5 is a valid CAS Registry Number.
InChI:InChI=1/C22H22O8/c1-25-16-4-10(5-17(26-2)21(16)27-3)18-11-6-14-15(30-9-29-14)7-12(11)20(23)13-8-28-22(24)19(13)18/h4-7,13,18-20,23H,8-9H2,1-3H3/t13-,18+,19+,20-/m0/s1
518-28-5Relevant articles and documents
Asymmetric total synthesis of (-)podophyllotoxin
Hadimani, Shreeshailkumar B.,Tanpure, Rajendra P.,Bhat, Sujata V.
, p. 4791 - 4794 (1996)
Asymmetric synthesis of podophyllotoxin is achieved through tandem conjugate addition of S (-) benzyl phenyl sulfoxide to but-2-en-4-olide.
Total synthesis of podophyllotoxin and select analog designs via C–H activation
Ting, Chi P.,Tschanen, Esther,Jang, Esther,Maimone, Thomas J.
, p. 3299 - 3308 (2019/05/15)
An account of our previously disclosed total synthesis of the aryltetralin lignan natural product podophyllotoxin, a building block used in the synthesis of the FDA-approved anticancer drug etoposide, is disclosed. A C–H activation disconnection was viewed as being amenable to the preparation of E-ring modified analogs but proved challenging to execute. Various insights into palladium-catalyzed C–H arylation reactions on complex scaffolds are reported ultimately leading to the implementation of this strategy and the synthesis of compounds inaccessible by semisynthetic means.
Divergent Asymmetric Syntheses of Podophyllotoxin and Related Family Members via Stereoselective Reductive Ni-Catalysis
Xiao, Jian,Cong, Xiao-Wei,Yang, Gui-Zhen,Wang, Ya-Wen,Peng, Yu
, p. 1651 - 1654 (2018/03/23)
A nickel-catalyzed reductive cascade approach to the efficient construction of diastereodivergent cores embedded in podophyllum lignans is developed for the first time. Their gram-scale access paved the way for unified syntheses of naturally occurring podophyllotoxin and other members.