Podophyllotoxin

Podophyllotoxin

Systematic (IUPAC) name
(10R,11R,15R,16R)-16-hydroxy-10-(3,4,5-trimethoxyphenyl)-4,6,13-trioxatetracyclo[7.7.0.03,7.011,15]hexadeca-1,3(7),8-trien-12-one
Clinical data
AHFS/Drugs.com	International Drug Names
MedlinePlus	a684055
Pregnancy category	C
Pharmacokinetic data
Biological half-life	1.0 to 4.5 hours.
Identifiers
CAS Number	518-28-5 Y
ATC code	D06BB04 (WHO)
PubChem	CID: 10607
DrugBank	DB01179 N
ChemSpider	10162 Y
UNII	L36H50F353 Y
KEGG	D05529 Y
ChEBI	CHEBI:50305 Y
ChEMBL	CHEMBL61 Y
Synonyms	(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
Chemical data
Formula	C22H22O8
Molecular mass	414.405 g/mol
SMILES COc1cc(cc(c1OC)OC)[C@@H]2c3cc4c(cc3[C@@H]([C@@H]5[C@@H]2C(=O)OC5)O)OCO4
InChI InChI=1S/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 Y Key:YJGVMLPVUAXIQN-XVVDYKMHSA-N Y
NY (what is this?)  (verify)

Podophyllotoxin (abbreviated as PPT), otherwise known as podofilox, is a non-alkaloid toxin lignan extracted from the roots and rhizomes of Podophyllum species. Under the trade names Condylox, a gel, and Wartec, a solution or cream, it is used on the skin as a topical treatment of external genital warts, caused by some types of the human papillomavirus (HPV), and other warts. PPT and its synthetic derivatives display a wide selection in medical applications such as purgative, vesicant, antirheumatic, antiviral, and antitumor agents. These derivatives include etoposide and teniposide. Their anticancer activity has been heavily under study and used in various chemotherapies, including lung cancer, lymphomas, and genital tumors.

Historically, podophyllin, a resin extracted from Podophyllum and Sinopodophyllum species primarily comprising podophyllotoxin, was also used.

It is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system.

Uses

Podophyllotoxin displays a range of activities such as cathartic, purgative, antiviral, vesicant, and antihelminthic. Additionally, podophyllotoxin and its derivatives are leads for anti-tumor agents such as etoposide and teniposide.

Podophyllin, a natural plant resin very high in podophyllotoxin content, has been used to remove genital warts since its efficacy was first demonstrated in 1942, although the reliability of this early report has been questioned. This requires one application of podophyllin resin per week to the warts by a health professional, which is then washed off after 4 to 6 hours. Petroleum jelly may be used to protect normal tissue near the warts from irritation. A health professional usually applies the resin once a week for at least 6 weeks or until warts disappear. It is unstable and therefore must be prepared shortly before use, which has possibly led to the lower efficacy shown in some clinical trials.

Podophyllin is also used to treat molluscum contagiosum in the genital area. As the molluscum lesions can sometimes be quite numerous, scarring and hypopigmentation become an issue with cryosurgery.

Contraindications

Contraindications include diabetes mellitus, poor circulation, corticosteroid therapy, pregnancy, breast-feeding, and application to bleeding warts, moles, birthmarks, or unusual warts with hair growing from them.

Adverse effects

The most common side effects near the application site are skin reactions, including burning, redness, pain, itching, swelling. There is some concern about the mutagenicity of some of the flavonoids in podophyllin. Application can be immediately followed by burning or itching. Small sores, itching and peeling skin can also follow.

Neither podophyllin resin nor podophyllotoxin lotions or gels are used during pregnancy because these medications can be harmful to the fetus.

Overdose and toxicity

In toxic doses, podophyllotoxin causes intense enteritis, with all its characteristic symptoms, and severe CNS depression, which may end in death. The treatment is symptomatic, there being no specific antidote.

Even when the toxin is used topically, it can be systemically absorbed into the body, and fatal and near-fatal reactions have been reported, particularly when it is used extensively or on mucous membranes.

Pharmacology

Mechanism of action

Podophyllotoxin and its derivatives display binding activity to the enzyme topoisomerase 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. Mutants resistant to either podophyllotoxin, or to its topoisomerase II inhibitory derivatives such as etoposide (VP-16), have been described in Chinese hamster cells. The mutually exclusive cross-resistance patterns of these mutants provide a highly specific mean to distinguish the two kinds of podophyllotoxin derivatives. Mutant Chinese hamster cells resistant to podophyllotoxin are affected in a protein P1 that was later identified as the mammalian HSP60 or chaperonin protein.

Physical and chemical properties

Structural characteristic

The structure of podophyllotoxin was first elucidated in the 1930s. 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.

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.

Biosynthesis

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. Several prior studies have suggested a common pathway starting from coniferyl alcohol being converted to (+)-pinoresinol in the presence of a one-electron oxidant 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, leading to podophyllotoxin.

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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. 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.

Natural abundance

It is present at concentrations of 0.3 to 1.0% by mass in the rhizome of American Mayapple (Podophyllum peltatum). 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.