Podophyllotoxin
Oxford A-Z of Medicinal Drugs:
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podophyllotoxin
A caustic agent (see keratolytics) that is the main active constituent of podophyllum. It is used to treat and dissolve warts affecting the penis or female genitalia. It is available, on prescription only, as a solution or cream for topical application.
Side effects:
local irritation may occur.
Precautions:
podophyllotoxin should not be used on open wounds or by women who are pregnant or breastfeeding. It is very irritant to the eyes.
Proprietary preparations:
Condyline; Warticon.
| plerixafor, placebo, pizotifen | |
| podophyllum, polyethylene glycols, polymyxin B sulphate |
Oxford Dictionary of Biochemistry:
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podophyllotoxin
a lignan found in the May apple, or American mandrake (Podophyllum peltatum). It is known in folk medicine as a cathartic and poison, and is useful in topical treatment of warts, including venereal warts; it may have antiviral action. In mammalian cells it inhibits assembly of tubulin into microtubules, and also nucleoside transport. It is used in the synthesis of Etoposide and Teniposide.
| podocalyxin, pocket, pneumococcus capsule swelling reaction | |
| poikilo+, poikilocyte, poikilosmotic |
Wikipedia on Answers.com:
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Podophyllotoxin
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| 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 cat. | ? |
| Legal status | ? |
| Pharmacokinetic data | |
| Half-life | 1.0 to 4.5 hours. |
| Identifiers | |
| CAS number | 518-28-5  |
| ATC code | D06BB04 |
| PubChem | CID 10607 |
| DrugBank | DB01179 |
| ChemSpider | 10162 |
| UNII | L36H50F353 |
| KEGG | D05529 |
| ChEBI | CHEBI:50305 |
| ChEMBL | CHEMBL61 |
| 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 |
| Mol. mass | 414.405 g/mol |
| SMILES | eMolecules & PubChem |
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Podophyllotoxin (abbreviated as PPT), otherwise known as podofilox, is a non-alkaloid toxin lignan extracted from the roots and rhizomes of Podophyllum species[1]. 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.
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Contents
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Natural abundance
It is present at concentrations of 0.3 to 1.0% by mass in the rhizome of American Mayapple (Podophyllum peltatum).[2][3] 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.[2]
Structural characteristic
The structure of podophyllotoxin was first elucidated in the 1930s.[4] 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. [5]
Derivatives of podophyllotoxin are synthesised 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. [5]
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 [6] 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 [6], 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.[6][7]
It is also used as a gel or solution to treat genital warts with noticeably shorter duration and fewer side effects.[8]
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[2].
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[2].Mutants resistant to either podophyllotoxin, or to its topoisomerase II inhibitory derivatives such as etoposide (VP-16), have been described in Chinese hamster cells.[9][10] The mutually exclusive cross-resistance patterns of these mutants provide a highly specific mean to distinguish the two kinds of podophyllotoxin derivatives.[11][10] Mutant Chinese hamster cells resistant to podophyllotoxin are affected in a protein P1 that was later identified as the mammalian HSP60 or chaperonin protein.[12][13]
References
- ^ Xu, H; Lv, M; Tian,X (2009). "A review on hemisynthesis, biosynthesis, biological activities, mode of action, and structure-activity relationship of podophyllotoxins: 2003-2007.". Current Medicinal Chemistry 16 (3): 327–349. doi:10.2174/092986709787002682. PMID 19149581.
- ^ a b c d Canel, C; Moraes, RM; Dayan, FE; Ferreira, D (2000). "Molecules of Interest: Podophyllotoxin". Phytochemistry 54 (2): 115–120.
- ^ J. L. Hartwell, A. W. Schrecker (1951). "Components of Podophyllin. V. The Constitution of Podophyllotoxin". Journal of the American Chemical Society 73 (6): 2909–2916. doi:10.1021/ja01150a143.
- ^ Borsche, W.; Niemann J. (1932). "Über Podophyllin". Justus Liebigs Ann. Chem. 494: 126–142. doi:10.1002/jlac.19324940113.
- ^ a b You, Y (2005). "Podophyllotoxin derivatives: current synthetic approaches for new anticancer agents.". Current Pharmaceutical Design 11 (13): 1695–1717. doi:10.2174/1381612053764724. PMID 15892669.
- ^ a b c Gordaliza M, García PA, del Corral JM, Castro MA, Gómez-Zurita MA (2004). "Podophyllotoxin: distribution, sources, applications and new cytotoxic derivatives". Toxicon 44 (4): 441–59. doi:10.1016/j.toxicon.2004.05.008. PMID 15302526. http://linkinghub.elsevier.com/retrieve/pii/S0041010104001953.
- ^ Damayanthi Y, Lown JW (June 1998). "Podophyllotoxins: current status and recent developments". Curr. Med. Chem. 5 (3): 205–52. PMID 9562603.
- ^ Xie FM, Zeng K, Chen ZL, et al. (2007). "[Treatment of recurrent condyloma acuminatum with solid lipid nanoparticle gel containing podophyllotoxin: a randomized double-blinded, controlled clinical trial]" (in Chinese). Nan Fang Yi Ke Da Xue Xue Bao 27 (5): 657–9. PMID 17545082.
- ^ Gupta, R.S., Ho, T.K.W., Moffat, M.R.K. and Gupta, R. (1982). Podophyllotoxin-resistant mutants of Chinese hamster ovary cells. Alteration in a microtubule-associated protein. J. Biol. Chem. 257: 1071-1078. [Abstract]
- ^ a b Gupta, R.S. (1983). Genetic, biochemical and cross-resistance studies with mutants of Chinese hamster ovary cells resistant to the anticancer drugs VM-26 and VP16-213. Cancer Res. 43: 1568-1574. [Abstract]
- ^ Gupta, R.S. (1983). Podophyllotoxin resistant mutants of Chinese hamster ovary cells: Cross resistance studies with various microtubule inhibitors and podophyllotoxin analogs. Cancer Res. 43: 505-512. [Abstract]
- ^ Picketts, D.J., Mayanil, C.S.K. and Gupta, R.S. (1989). Molecular cloning of a Chinese hamster mitochondrial protein related to the "chaperonin" family of bacterial and plant proteins. J. Biol. Chem. 264: 12001-12008. [Abstract]
- ^ Jindal, S., Dudani, A.K., Singh, B., Harley, C.B. and Gupta, R.S (1989). Primary structure of a human mitochondrial protein homologous to the bacterial and plant chaperonins and to the 65 kDa mycobacterial antigen. Mol. Cell Biol. 9: 2279-2283. [Abstract]
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Market University Press. © 2000, 2003, 2010 An A-Z of Medicinal Drugs. All rights reserved.
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Saunders Veterinary Dictionary
Saunders Comprehensive Veterinary Dictionary 3rd Edition. Copyright © 2007 by D.C. Blood, V.P. Studdert and C.C. Gay, Elsevier. All rights reserved.
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