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Clinical data
Trade names Condylox, Wartec, others
Other names (5R,5aR,8aR,9R)-9-hydroxy-5-(3,4,5-trimethoxyphenyl)-5,8,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one
AHFS/Drugs.com Monograph
MedlinePlus a684055
  • C
ATC code
Pharmacokinetic data
Elimination half-life 1.0 to 4.5 hours.
CAS Number
  • 518-28-5 ☑Y
PubChem CID
  • 10607
  • DB01179 ☒N
  • 10162 ☑Y
  • L36H50F353
  • D05529 ☑Y
  • CHEBI:50305 ☑Y
  • ChEMBL61 ☑Y
CompTox Dashboard (EPA)
  • DTXSID3045645
ECHA InfoCard 100.007.502
Chemical and physical data
Formula C22H22O8
Molar mass 414.405 g/mol g·mol−1
3D model (JSmol)
  • Interactive image
Melting point 183.3 to 184 °C (361.9 to 363.2 °F)
 ☒N☑Y (what is this?)   (verify)

Podophyllotoxin (PPT), also known as podofilox, is a medical cream that is used to treat genital warts and molluscum contagiosum.[1] It is not recommended in HPV infections without external warts.[1] It can be applied either by a healthcare provider or the person themselves.[1]

It is a non-alkaloid toxin lignan extracted from the roots and rhizomes of Podophyllum species.[2] A less refined form known as podophyllum resin is also available, but has greater side effects.[3][4]

Podophyllotoxin was isolated in 1880.[5] In the United Kingdom the price for the NHS of 3.5 ml of medication is about 14.49 pounds.[6] In the United States the price of a course of treatment is more than $200.[7]

Medical uses

Podophyllotoxin possesses a large number of medical applications, as it is able to stop replication of both cellular and viral DNA by binding necessary enzymes. It can additionally destabilize microtubules and prevent cell division. Because of these interactions it is considered an antimitotic drug. Podophyllotoxin and its derivatives are used as cathartic, purgative, antiviral agent, vesicant, antihelminthic, and antitumor agents. Podophyllotoxin derived antitumor agents include etoposide and teniposide.[8][9] These drugs have been successfully used in therapy against numerous cancers including testicular, breast, pancreatic, lung, stomach, and ovarian cancers.[10]

Derivatives of podophyllotoxin that have been engineered for their ability to fight tumors.[11]

Podophyllotoxin cream is commonly prescribed as a potent topical antiviral. It is used for the treatment of HPV infections with external warts as well as molluscum contagisum infections.[1] PPT cream is highly effective with minimal side effects, which are typically limited to itching, irritation, and redness.[12] 0.5% PPT cream is prescribed for twice daily applications for 3 days followed by 4 days with no application, this weekly cycle is repeated for 4 weeks.[13] It can also be prescribed as a gel, as opposed to cream. PPT is also sold under the names condyline and warticon.[14]

Adverse effects

The most common side effects of podophyllotoxin cream are typically limited to irritation of tissue surrounding the application site, including burning, redness, pain, itching, swelling.[15] Application can be immediately followed by burning or itching. Small sores, itching and peeling skin can also follow, for these reasons it is recommended that application be done in a way that limits contact with surrounding, uninfected tissue[16]

Neither podophyllin resin nor podophyllotoxin lotions or gels are used during pregnancy because these medications have been shown to be embroytoxic in both mice and rats. Additionally, antimitotic agents are not typically recommended during pregnancy.[17] Additionally, it has not been determined if podophyllotoxin can pass into breast milk from topical applications and therefore it is not recommended for breastfeeding women.[18]

Podophyllotoxin cream is safe for topical use; however, it can cause CNS depression as well as enteritis if ingested. The podophyllum resin from which podophyllotoxin is derived has the same effect.[19]

Mechanism of action

Podophyllotoxin destabilizes microtubules by binding tubulin and thus preventing cell division.[20][21] In contrast, some of its derivatives display binding activity to the enzyme topoisomerase II (Topo II) during the late S and early G2 stage. For instance, etoposide binds and stabilizes the temporary DNA break caused by the enzyme, disrupts the reparation of the break through which the double-stranded DNA passes, and consequently stops DNA unwinding and replication.[22] Mutants resistant to either podophyllotoxin, or to its topoisomerase II inhibitory derivatives such as etoposide (VP-16), have been described in Chinese hamster cells.[23][24] The mutually exclusive cross-resistance patterns of these mutants provide a highly specific means to distinguish the two kinds of podophyllotoxin derivatives.[24][25] Mutant Chinese hamster cells resistant to podophyllotoxin are affected in a protein P1 that was later identified as the mammalian HSP60 or chaperonin protein.[26][27][28] Furthermore, podophyllotoxin is classified as an arytetralin lignan for its ability to bind and deactivate DNA.[29] It and its derivates bind Topo II and prevent its ability to catalyze rejoining of DNA that has been broken for replication. Lastly, experimental evidence has shown that these arytetralin lignans can interact with cellular factors to create chemical DNA adducts, thus further deactivating DNA.[29]


Structural characteristic

The structure of podophyllotoxin was first elucidated in the 1930s.[30] Podophyllotoxin bears four consecutive chiral centers, labelled C-1 through C-4 in the following image. The molecule also contains four almost planar fused rings. The podophyllotoxin molecule includes a number of oxygen containing functional groups: an alcohol, a lactone, three methoxy groups, and an acetal.[31]

Ring assignment and numbering of podophyllotoxin

Derivatives of podophyllotoxin are synthesized as properties of the rings and carbon 1 through 4 are diversified. For example, ring A is not essential to antimitotic activity. Aromatization of ring C leads to loss of activity, possibly from ring E no longer being placed on the axial position. In addition, the stereochemistry at C-2 and C-3 configures a trans-lactone, which has more activity than the cis counterpart. Chirality at C-1 is also important as it implies an axial position for ring E.[31]


The biosynthetic route of podophyllotoxin was not completely eludicidated for many years; however, in September 2015, the identity of the six missing enzymes in podophyllotoxin biosynthesis were reported for the first time.[32] Several prior studies have suggested a common pathway starting from coniferyl alcohol being converted to (+)-pinoresinol in the presence of a one-electron oxidant [8] through dimerization of stereospecific radical intermediate. Pinoresinol is subsequently reduced in the presence of co-factor NADPH to first lariciresinol, and ultimately secoisolariciresinol. Lactonization on secoisolariciresinol gives rise to matairesinol. Secoisolariciresinol is assumed to be converted to yatein through appropriate quinomethane intermediates,[8] leading to podophyllotoxin.

Proposed biosynthetic pathway leading to podophyllotoxin

A sequence of enzymes involved has been reported to be dirigent protein (DIR), to convert coniferyl alcohol to (+)-pinocresol, which is converted by pinocresol-lariciresinol reductase (PLR) to (-)-secoisolariciresinol, which is converted by sericoisolariciresinol dehydrogenase (SDH) to (-)-matairesinol, which is converted by CYP719A23 to (-)-pluviatolide, which is likely converted by Phex13114 (OMT1) to (-)-yatein, which is converted by Phex30848 (2-ODD) to (-)-deoxypodophyllotoxin.[32] Though not proceeding through the last step of producing podophyllotoxin itself, a combination of six genes from the mayapple enabled production of the etoposide aglycone in tobacco plants.[32]

Chemical synthesis

Podophyllotoxin has been successfully synthesized in a laboratory, however, synthesis mechanisms have required a large number of steps which has resulted in low overall yield. Because of this challenge it is still more efficient to obtain podophyllotoxin from natural sources.[10] Four routes have been used to synthesize podophyllotoxin with varying success. It has been synthesized using an oxo ester route,[33] lactonization of a dihydroxy acid,[34] cyclization of a conjugate addition product,[35] and utilization of a Diels-Alder reaction.[36]

Natural abundance

It is present at concentrations of 0.3 to 1.0% by mass in the rhizome of American Mayapple (Podophyllum peltatum).[22][37] Another common source of podophyllotoxin is the rhizomes of Sinopodophyllum hexandrum Royle (Berberidaceae).

It is biosynthesized from two molecules of coniferyl alcohol by phenolic oxidative coupling and a series of oxidations, reductions and methylations.[22]


  1. ^ a b c d "Podofilox". The American Society of Health-System Pharmacists. Retrieved 8 December 2016.
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  3. ^ "Podophyllum Resin". The American Society of Health-System Pharmacists. Retrieved 8 December 2016.
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  33. ^ Kende AS, King ML, Curran DP (June 1981). "Total synthesis of (.+-.)-4'-demethyl-4-epipodophyllotoxin by insertion-cyclization". The Journal of Organic Chemistry. 46 (13): 2826–2828. doi:10.1021/jo00326a056.
  34. ^ Macdonald DI, Durst T (August 1988). "A highly stereoselective synthesis of podophyllotoxin and analogues based on an intramolecular Diels-Alder reaction". The Journal of Organic Chemistry. 53 (16): 3663–3669. doi:10.1021/jo00251a003.
  35. ^ Ziegler FE, Schwartz JA (March 1978). "Synthetic studies on lignan lactones: aryl dithiane route to (.+-.)-podorhizol and (.+-.)-isopodophyllotoxone and approaches to the stegane skeleton". The Journal of Organic Chemistry. 43 (5): 985–991. doi:10.1021/jo00399a040.
  36. ^ Klemm LH, Olson DR, White DV (December 1971). "Intramolecular Diels-Alder reactions. VII. Electroreduction of .alpha.,.beta.-unsaturated esters. I. Synthesis of rac-deoxypicropodophyllin by intramolecular Diels-Alder reaction plus trans addition of hydrogen". The Journal of Organic Chemistry. 36 (24): 3740–3743. doi:10.1021/jo00823a017.
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Further reading

  • Kelly M, Hartwell JL (February 1954). "The biological effects and the chemical composition of podophyllin: a review". Journal of the National Cancer Institute. 14 (4): 967–1010. PMID 13233838.
  • Hartwell JL, Schrecker AW (1951). "Components of Podophyllin. V. The Constitution of Podophyllotoxin". Journal of the American Chemical Society. 73 (6): 2909–2916. doi:10.1021/ja01150a143.
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