Chemistry:Podophyllotoxin

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Short description: Chemical compound
Podophyllotoxin
Podophyllotoxin2DCSD.svg
Clinical data
Trade namesCondylox,[1] 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.comMonograph
MedlinePlusa684055
Pregnancy
category
  • C
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Elimination half-life1.0 to 4.5 hours.
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC22H22O8
Molar mass414.410 g·mol−1
3D model (JSmol)
Melting point183.3 to 184 °C (361.9 to 363.2 °F)
 ☒N☑Y (what is this?)  (verify)

Podophyllotoxin (PPT) is the active ingredient in Podofilox, which is a medical cream that is used to treat genital warts and molluscum contagiosum.[2] It is not recommended in HPV infections without external warts.[2] It can be applied either by a healthcare provider or the person themselves.[2]

It is a non-alkaloid toxin lignin extracted from the roots and rhizomes of Podophyllum species.[3] A less refined form known as podophyllum resin is also available, but has greater side effects.[4][5]

Podophyllotoxin was first isolated in pure form in 1880 by Valerian Podwyssotzki (1818 – 28 January 1892), a Polish-Russian privatdozent at the University of Dorpat (now: Tartu, Estonia) and assistant at the Pharmacological Institute there.[6][7][8]

It is on the World Health Organization's List of Essential Medicines.[9]

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, although modern medicine instead use less orally toxic derivatives when such effect is wanted.[10]

Podophyllotoxin cream is commonly prescribed as a potent topical antiviral.[11] It is used for the treatment of HPV infections with external warts as well as molluscum contagisum infections.[11] 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.[12] It can also be prescribed as a gel, as opposed to cream. PPT is also sold under the names condyline and warticon.[13]

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.[14] 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[15]

Neither podophyllin resin nor podophyllotoxin lotions or gels are used during pregnancy because these medications have been shown to be embryotoxic in both mice and rats. Additionally, antimitotic agents are not typically recommended during pregnancy.[16] 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.[17]

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.[18]

Mechanism of action

Podophyllotoxin destabilizes microtubules by binding tubulin and thus preventing cell division.[19][20] 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.[21] Mutants resistant to either podophyllotoxin, or to its topoisomerase II inhibitory derivatives such as etoposide (VP-16), have been described in Chinese hamster cells.[22][23] The mutually exclusive cross-resistance patterns of these mutants provide a highly specific means to distinguish the two kinds of podophyllotoxin derivatives.[23][24] Mutant Chinese hamster cells resistant to podophyllotoxin are affected in a protein P1 that was later identified as the mammalian HSP60 or chaperonin protein.[25][26][27]

Furthermore, podophyllotoxin is classified as an arytetralin lignan for[dubious – discuss] its ability to bind and deactivate DNA.[28] 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.[28]

Chemistry

Structural characteristic

The structure of podophyllotoxin was first elucidated in the 1930s.[29] 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.[30]

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.[30]

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.[31] Several prior studies have suggested a common pathway starting from coniferyl alcohol being converted to (+)-pinoresinol in the presence of a one-electron oxidant [10] 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,[10] 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.[31] 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.[31]

Chemical synthesis

Podophyllotoxin has been successfully synthesized in a laboratory; however, synthesis mechanisms require many steps, resulting in a low overall yield. It therefore remains more efficient to obtain podophyllotoxin from natural sources.[32]

Four routes have been used to synthesize podophyllotoxin with varying success: an oxo ester route,[33] lactonization of a dihydroxy acid,[34] cyclization of a conjugate addition product,[35] and a Diels-Alder reaction.[36]

Derivatives

Podophyllotoxin and its derivatives are used as cathartic, purgative, antiviral agent, vesicant, antihelminthic, and antitumor agents. Podophyllotoxin derived antitumor agents include etoposide and teniposide.[10][37] These drugs have been successfully used in therapy against numerous cancers including testicular, breast, pancreatic, lung, stomach, and ovarian cancers.[32]

Derivatives of podophyllotoxin that have been engineered for their ability to fight tumors.[38]

Natural abundance

Podophyllotoxin is present at concentrations of 0.3% to 1.0% by mass in the rhizome of the American mayapple (Podophyllum peltatum).[21][39] Another common source is the rhizome 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.[21]

References

  1. ↑ "What is Condylox?" (in DE). https://deutschemedz.de/condylox/. 
  2. ↑ 2.0 2.1 2.2 "Podofilox". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/podofilox.html. 
  3. ↑ "A review on hemisynthesis, biosynthesis, biological activities, mode of action, and structure-activity relationship of podophyllotoxins: 2003-2007". Current Medicinal Chemistry 16 (3): 327–49. 2009. doi:10.2174/092986709787002682. PMID 19149581. 
  4. ↑ "Podophyllum Resin". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/podophyllum-resin.html. 
  5. ↑ WHO Model Formulary 2008. World Health Organization. 2009. p. 307. ISBN 9789241547659. 
  6. ↑ See:
  7. ↑ Anticancer Agents from Natural Products, Second Edition (2 ed.). CRC Press. 2011. p. 97. ISBN 9781439813836. https://books.google.com/books?id=qC7NBQAAQBAJ&pg=PA97. 
  8. ↑ "Podophyllotoxin: History, Recent Advances and Future Prospects". Biomolecules 11 (4): 603. April 2021. doi:10.3390/biom11040603. PMID 33921719. 
  9. ↑ World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. 2021. WHO/MHP/HPS/EML/2021.02. 
  10. ↑ 10.0 10.1 10.2 10.3 "Podophyllotoxin: distribution, sources, applications and new cytotoxic derivatives". Toxicon 44 (4): 441–59. September 2004. doi:10.1016/j.toxicon.2004.05.008. PMID 15302526. 
  11. ↑ 11.0 11.1 "Podophyllotoxin: a novel potential natural anticancer agent". Avicenna Journal of Phytomedicine 7 (4): 285–294. 2016. PMID 28884079. 
  12. ↑ "Podofilox Monograph for Professionals - Drugs.com". Drugs.com. https://www.drugs.com/monograph/podofilox.html. 
  13. ↑ "Podophyllotoxin for anogenital warts; Podophyllotoxin info". https://patient.info/medicine/podophyllotoxin-for-anogenital-warts-condyline-warticon. 
  14. ↑ "Condyloma eradication: self-therapy with 0.15-0.5% podophyllotoxin versus 20-25% podophyllin preparations--an integrated safety assessment". Regulatory Toxicology and Pharmacology 33 (2): 117–37. April 2001. doi:10.1006/rtph.2000.1446. PMID 11350195. 
  15. ↑ "PRODUCT INFORMATION WARTEC® SOLUTION". GlaxoSmithKline Australia Pty Ltd. http://www.gsk.com.au/resources.ashx/prescriptionmedicinesproductschilddataproinfo/1639/FileName/BF1A2ECC4097B192BB4A4E85FB9F0AEF/Wartec_Solution_PI_004_Approved.pdf. 
  16. ↑ "Is Podophyllin Safe for Use in Pregnancy?". Archives of Dermatology 125 (7): 1000–1. July 1989. doi:10.1001/archderm.1989.01670190134022. PMID 2742385. 
  17. ↑ "Podophyllotoxin | DermNet New Zealand". https://www.dermnetnz.org/topics/podophyllotoxin/. 
  18. ↑ "Podophyllum toxicity: case report and literature review". The Journal of Family Practice 9 (2): 237–40. August 1979. PMID 458391. 
  19. ↑ "Podophyllotoxin: a novel potential natural anticancer agent". Avicenna Journal of Phytomedicine 7 (4): 285–294. 2017-06-01. doi:10.22038/ajp.2017.8779. PMID 28884079. 
  20. ↑ "Antitumor properties of podophyllotoxin and related compounds". Current Pharmaceutical Design 6 (18): 1811–1839. December 2000. doi:10.2174/1381612003398582. PMID 11102564. 
  21. ↑ 21.0 21.1 21.2 "Molecules of Interest: Podophyllotoxin". Phytochemistry 54 (2): 115–120. 2000. doi:10.1016/s0031-9422(00)00094-7. PMID 10872202. 
  22. ↑ "Podophyllotoxin-resistant mutants of Chinese hamster ovary cells. Alteration in a microtubule-associated protein". The Journal of Biological Chemistry 257 (2): 1071–1078. January 1982. doi:10.1016/S0021-9258(19)68309-2. PMID 7054166. 
  23. ↑ 23.0 23.1 "Genetic, biochemical, and cross-resistance studies with mutants of Chinese hamster ovary cells resistant to the anticancer drugs, VM-26 and VP16-213". Cancer Research 43 (4): 1568–1574. April 1983. PMID 6831403. 
  24. ↑ "Podophyllotoxin-resistant mutants of Chinese hamster ovary cells: cross-resistance studies with various microtubule inhibitors and podophyllotoxin analogues". Cancer Research 43 (2): 505–512. February 1983. PMID 6848174. 
  25. ↑ "Molecular cloning of a Chinese hamster mitochondrial protein related to the "chaperonin" family of bacterial and plant proteins". The Journal of Biological Chemistry 264 (20): 12001–12008. July 1989. doi:10.1016/S0021-9258(18)80166-1. PMID 2568357. 
  26. ↑ "Primary structure of a human mitochondrial protein homologous to the bacterial and plant chaperonins and to the 65-kilodalton mycobacterial antigen". Molecular and Cellular Biology 9 (5): 2279–2283. May 1989. doi:10.1128/mcb.9.5.2279. PMID 2568584. 
  27. ↑ "Chapter 54: Cancer Chemotherapy". Pharmacology examination & board review. (10th ed.). New York: McGraw-Hill Medical. 2013. ISBN 978-0-07-178923-3. 
  28. ↑ 28.0 28.1 "Aryltetralin lignans: chemistry, pharmacology and biotransformations". Current Medicinal Chemistry 8 (11): 1363–1381. September 2001. doi:10.2174/0929867013372292. PMID 11562272. 
  29. ↑ "Über Podophyllin". Justus Liebigs Ann. Chem. 494: 126–142. 1932. doi:10.1002/jlac.19324940113. 
  30. ↑ 30.0 30.1 "Podophyllotoxin derivatives: current synthetic approaches for new anticancer agents". Current Pharmaceutical Design 11 (13): 1695–717. 2005. doi:10.2174/1381612053764724. PMID 15892669. 
  31. ↑ 31.0 31.1 31.2 "Six enzymes from mayapple that complete the biosynthetic pathway to the etoposide aglycone". Science 349 (6253): 1224–8. September 2015. doi:10.1126/science.aac7202. PMID 26359402. Bibcode: 2015Sci...349.1224L. 
  32. ↑ 32.0 32.1 "Podophyllotoxin". Phytochemistry 54 (2): 115–20. May 2000. doi:10.1016/s0031-9422(00)00094-7. PMID 10872202. 
  33. ↑ "Total synthesis of (.+-.)-4'-demethyl-4-epipodophyllotoxin by insertion-cyclization". The Journal of Organic Chemistry 46 (13): 2826–2828. June 1981. doi:10.1021/jo00326a056. 
  34. ↑ "A highly stereoselective synthesis of podophyllotoxin and analogues based on an intramolecular Diels-Alder reaction". The Journal of Organic Chemistry 53 (16): 3663–3669. August 1988. doi:10.1021/jo00251a003. 
  35. ↑ "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. March 1978. doi:10.1021/jo00399a040. 
  36. ↑ "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. December 1971. doi:10.1021/jo00823a017. 
  37. ↑ "Podophyllotoxins: current status and recent developments". Current Medicinal Chemistry 5 (3): 205–52. June 1998. doi:10.2174/0929867305666220314204426. PMID 9562603. 
  38. ↑ "Recent progress on C-4-modified podophyllotoxin analogs as potent antitumor agents". Medicinal Research Reviews 35 (1): 1–62. January 2015. doi:10.1002/med.21319. PMID 24827545. 
  39. ↑ "Components of Podophyllin. V. The Constitution of Podophyllotoxin". Journal of the American Chemical Society 73 (6): 2909–2916. 1951. doi:10.1021/ja01150a143. 

Further reading



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