Podophyllotoxin

Podophyllotoxin

File:Podophyllotoxin acsv.svg
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
Pharmacokinetic data
Biological half-life	1.0 to 4.5 hours.
Identifiers
CAS Number	518-28-5
ATC code	D06BB04 (WHO)
PubChem	CID 10607
DrugBank	APRD01189
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
Molar mass	414.405 g/mol[[]]
(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 name Condylox, a topical gel, it is used on the skin to treat external genital warts, caused by some types of the human papillomavirus (HPV). PPT and its derivatives display a wide selection in medical applications such as purgative, vesicant, antirheumatic, antiviral, and antitumor agents. These derivatives include etoposide, teniposide, and etopophos. Their anticancer activity has been heavily under study and used in various chemotherapies, including lung cancer, lymphomas, and genital tumors.

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 Podophyllum hexandrum Royle (Berberidaceae).

It is synthesized biologically from two molecules of coniferyl alcohol by phenolic oxidative coupling and a series of oxidations, reductions and methylations.

Structural characteristic

The structure of podophyllotoxin was first elucidated in the 1930s. Podophyllotoxin bears a four consecutive chiral centers, labelled C-1 through C-4. The molecule also contains four almost planar fused rings. Four ends of podophyllotoxin have oxygen atoms at the functional groups dioxoles, methoxys, lactone, and secondary alcohol.

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.

Biosynthesis

Although the biosynthetic route of podophyllotoxin has yet to be completely elucidated, several 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.

Proposed biosynthetic pathway leading to podophyllotoxin.

Side effects

Application can be immediately followed by burning or itching. Small sores, itching and peeling skin can also follow. Ingestion or entering the blood stream in small amounts through the dermis can cause fatal poisoning, symptoms include shortness of breath, rapid heart rate and shivers. Most people using the gel do not report these side effects.

Usages and applications

Podophyllotoxin displays a range of activities such as cathartic, purgative, antiviral, vesicant, and antihelminthic. Additionally, the lignan and its derivatives are exciting leads for anti-tumor agent. For instance, podophyllotoxin is the pharmacological precursor for the important anticancer drug etoposide.

It is also used as a gel or solution to treat genital warts with noticeably shorter duration and fewer side effects.

Mechanism of action

Podophyllotoxin's anticancer property can be attributed to the inhibition of tubulin polymerization. As podophyllotoxin binds to the tubulin, microtubule formation is prevented. Consequently, podophyllotoxin arrests the cell cycle in the metaphase.

Podophyllotoxin 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 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.

References

de:Podophyllotoxin pl:Podofilotoksyna