Podophyllotoxin

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Podophyllotoxin
Podophyllotoxin2DCSD.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
Clinical data
AHFS/Drugs.com International Drug Names
MedlinePlus a684055
Legal status ?
Pharmacokinetic data
Half-life 1.0 to 4.5 hours.
Identifiers
CAS number 518-28-5 YesY
ATC code D06BB04
PubChem CID 10607
DrugBank DB01179
ChemSpider 10162 YesY
UNII L36H50F353 YesY
KEGG D05529 YesY
ChEBI CHEBI:50305 YesY
ChEMBL CHEMBL61 YesY
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
 N (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.[1] 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, 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[edit]

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 biosynthesized from two molecules of coniferyl alcohol by phenolic oxidative coupling and a series of oxidations, reductions and methylations.[2]

Structural characteristic[edit]

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]

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.[5]

Biosynthesis[edit]

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.

Proposed biosynthetic pathway leading to podophyllotoxin.

Side effects[edit]

Application can be immediately followed by burning or itching. Small sores, itching and peeling skin can also follow.[7]

Usages and applications[edit]

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][8]

Mechanism of action[edit]

Etoposide, a semisynthetic derivative of podophyllotoxin, induces DNA breakage through its inhibition of topoisomerase II. The drug is most active in the late S and early G2 phases of the cell cycle. Teniposide is an analog with very similar pharmacologic characteristics. [9]

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.[10][11] The mutually exclusive cross-resistance patterns of these mutants provide a highly specific mean to distinguish the two kinds of podophyllotoxin derivatives.[11][12] Mutant Chinese hamster cells resistant to podophyllotoxin are affected in a protein P1 that was later identified as the mammalian HSP60 or chaperonin protein.[13][14]

References[edit]

  1. ^ 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. 
  2. ^ a b c Canel, C; Moraes, RM; Dayan, FE; Ferreira, D (2000). "Molecules of Interest: Podophyllotoxin". Phytochemistry 54 (2): 115–120. doi:10.1016/s0031-9422(00)00094-7. 
  3. ^ 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. 
  4. ^ Borsche, W.; Niemann J. (1932). "Über Podophyllin". Justus Liebigs Ann. Chem. 494: 126–142. doi:10.1002/jlac.19324940113. 
  5. ^ 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. 
  6. ^ 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. 
  7. ^ "PRODUCT INFORMATION WARTEC® SOLUTION". GlaxoSmithKline Australia Pty Ltd. Retrieved 6 January 2013. 
  8. ^ Damayanthi Y, Lown JW (June 1998). "Podophyllotoxins: current status and recent developments". Curr. Med. Chem. 5 (3): 205–52. PMID 9562603. 
  9. ^ Anthony J. Trevor, Bertram G. Katzung, Marieke Kruidering-Hall, Susan B. Masters. Chapter 54: Cancer Chemotherapy. Katzung & Trevor's Pharmacology: Examination & Board Review, 10th edition.
  10. ^ 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]
  11. ^ 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]
  12. ^ 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]
  13. ^ 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]
  14. ^ 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]