Podophyllotoxin
Encyclopedia
Podophyllotoxin 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 wart
s, 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.
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, reduction
s and methylation
s.
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.
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.
.
It is also used as a gel
or solution
to treat genital warts with noticeably shorter duration and fewer side effects.
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.
Alkaloid
Alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...
toxin
Toxin
A toxin is a poisonous substance produced within living cells or organisms; man-made substances created by artificial processes are thus excluded...
lignan
Lignan
The lignans are a group of chemical compounds found in plants. Lignans are one of the major classes of phytoestrogens, which are estrogen-like chemicals and also act as antioxidants. The other classes of phytoestrogens are the isoflavones and coumestans...
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 wart
Genital wart
Genital warts is a highly contagious sexually transmitted disease caused by some sub-types of human papillomavirus . It is spread through direct skin-to-skin contact during oral, genital, or anal sex with an infected partner...
s, caused by some types of the human papillomavirus
Human papillomavirus
Human papillomavirus is a member of the papillomavirus family of viruses that is capable of infecting humans. Like all papillomaviruses, HPVs establish productive infections only in keratinocytes of the skin or mucous membranes...
(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
Etoposide
Etoposide phosphate is an anti-cancer agent. It is known in the laboratory as a topoisomerase poison. Etoposide is often incorrectly referred to as a topoisomerase inhibitor in order to avoid using the term "poison" in a clinical setting...
, teniposide
Teniposide
Teniposide is a chemotherapeutic medication mainly used in the treatment of childhood acute lymphocytic leukemia . It is in a class of drugs known as podophyllotoxin derivatives and slows the growth of cancer cells in the body....
, 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 rhizomeRhizome
In botany and dendrology, a rhizome is a characteristically horizontal stem of a plant that is usually found underground, often sending out roots and shoots from its nodes...
of American Mayapple (Podophyllum peltatum). Another common source of podophyllotoxin is the rhizomes of Podophyllum hexandrum Royle (Berberidaceae
Berberidaceae
Berberidaceae are a family of 15 genera flowering plants commonly called the barberry family. This family is in the order Ranunculales. The family contains about 570 species, of which the majority are in Berberis...
).
It is synthesized biologically from two molecules of coniferyl alcohol
Coniferyl alcohol
Coniferyl alcohol is an organic compound. This colourless crystalline solid is a phytochemical, one of the monolignols. It is synthethized via the phenylpropanoid biochemical pathway. When copolymerized with related aromatic compounds, coniferyl alcohol forms lignin or lignans...
by phenolic oxidative coupling and a series of oxidations, reduction
Redox
Redox reactions describe all chemical reactions in which atoms have their oxidation state changed....
s and methylation
Methylation
In the chemical sciences, methylation denotes the addition of a methyl group to a substrate or the substitution of an atom or group by a methyl group. Methylation is a form of alkylation with, to be specific, a methyl group, rather than a larger carbon chain, replacing a hydrogen atom...
s.
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.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 alcoholConiferyl alcohol
Coniferyl alcohol is an organic compound. This colourless crystalline solid is a phytochemical, one of the monolignols. It is synthethized via the phenylpropanoid biochemical pathway. When copolymerized with related aromatic compounds, coniferyl alcohol forms lignin or lignans...
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.
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 etoposideEtoposide
Etoposide phosphate is an anti-cancer agent. It is known in the laboratory as a topoisomerase poison. Etoposide is often incorrectly referred to as a topoisomerase inhibitor in order to avoid using the term "poison" in a clinical setting...
.
It is also used as a gel
Gel
A gel is a solid, jelly-like material that can have properties ranging from soft and weak to hard and tough. Gels are defined as a substantially dilute cross-linked system, which exhibits no flow when in the steady-state...
or solution
Solution
In chemistry, a solution is a homogeneous mixture composed of only one phase. In such a mixture, a solute is dissolved in another substance, known as a solvent. The solvent does the dissolving.- Types of solutions :...
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
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
passes, and consequently stops DNA unwinding and replication.