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INDUSTRIAL PRODUCTION,ESTIMATION AND UTILIZATION OF PODOPHYLLOTOXIN

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INDUSTRIAL PRODUCTION,ESTIMATION AND
UTILIZATION OF
PODOPHYLLOTOXIN
(BP504 T. PHARMACOGNOSY AND PHYTOCHEMISTRY )
SOURCE
• Podophyllotoxin (PPT), also known as podofilox,
• It is a non-alkaloid toxin lignan extracted from the roots
and dried rhizomes of Podophyllum hexandrum.
Family:Berberidaceae.
A less refined form known as podophyllum resin is also
available, but has greater side effects.
Chemical structure and Molecular composition
Formula C22H22O8
Molar mass 414.410 g·mol−1
Melting point 183.3 to 184 °C (361.9 to 363.2 °F)
Mechanism of action
• Podophyllotoxin (PDT) destabilizes microtubules by binding tubulin
and thus preventing cell division.
• In contrast, some of its derivatives display binding activity to the
enzyme topoisomerase II (TPI- II) during the late S and early G2
stage.
• It inhibits the activity and increases the level of TPI-II enzyme and
increases DNA Cleavage complex and there by leads to genetic
alteration and cell death
MECHANISM OF ACTION OF Podophyllotoxin PDT
Industrial production of Podophyllotoxin
• The use of biotechnological approaches for the production of
podophyllotoxin using cell cultures,
• Organ cultures, and
• Biotransformation route or
• By manipulating biosynthetic pathway proves to be an attractive
alternative for production of Podophyllotoxin

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INDUSTRIAL PRODUCTION,ESTIMATION AND UTILIZATION OF PODOPHYLLOTOXIN

  • 1. INDUSTRIAL PRODUCTION,ESTIMATION AND UTILIZATION OF PODOPHYLLOTOXIN (BP504 T. PHARMACOGNOSY AND PHYTOCHEMISTRY )
  • 2. SOURCE • Podophyllotoxin (PPT), also known as podofilox, • It is a non-alkaloid toxin lignan extracted from the roots and dried rhizomes of Podophyllum hexandrum. Family:Berberidaceae. A less refined form known as podophyllum resin is also available, but has greater side effects.
  • 3. Chemical structure and Molecular composition Formula C22H22O8 Molar mass 414.410 g·mol−1 Melting point 183.3 to 184 °C (361.9 to 363.2 °F)
  • 4. Mechanism of action • Podophyllotoxin (PDT) destabilizes microtubules by binding tubulin and thus preventing cell division. • In contrast, some of its derivatives display binding activity to the enzyme topoisomerase II (TPI- II) during the late S and early G2 stage. • It inhibits the activity and increases the level of TPI-II enzyme and increases DNA Cleavage complex and there by leads to genetic alteration and cell death
  • 5. MECHANISM OF ACTION OF Podophyllotoxin PDT
  • 6. Industrial production of Podophyllotoxin • The use of biotechnological approaches for the production of podophyllotoxin using cell cultures, • Organ cultures, and • Biotransformation route or • By manipulating biosynthetic pathway proves to be an attractive alternative for production of Podophyllotoxin
  • 7. Industrial Production of podophyllotoxin from Podophyllum hexandrum METHODS INVOLVED IN THE PRODUCTION: • Bio synthetic pathway • Use of callus and cell suspension cultures for the production of podophyllotoxin • Use of transgenic hairy roots for the production of podophyllotoxin • Podophyllotoxin production using biotransformation approach • Metabolic engineering considerations for the production of podophyllotoxin
  • 8. Bio synthetic Pathway • Podophyllotoxin belongs to lignan group of compounds. • Lignans are dimerization products of two phenylpropane units linked by carbon atoms of their side chain. • Most of the pathways proposed involve phenolic oxidative coupling of C6-C3 monomers via shikimic acid pathway. • Production of optically active lignan dimers is enzyme-controlled reaction. • A series of compounds of considerable medicinal and commercial interest as clinically useful anticancer drugs are formed by reductive dimerization of cinnamic alcohols or cinnamic acid
  • 10. • Roots of P. hexandrum for the production of podophyllotoxin in undifferentiated callus and cell suspension cultures has been reported. • It has also been reported that coniferin was a substrate for podophyllotoxin production • Callus cultures of P. hexandrum Royle were very difficult to initiate. CALLUS AND CELL SUSPENSION CULTURES
  • 11. CALLUS AND CELL SUSPENSION CULTURES • Cell suspensions were initiated by transferring the callus to same liquid medium agitated on a shaker at 150 rpm. • After ten passages homogeneous and undifferentiated suspensions were obtained. • Good podophyllotoxin producing cultures were dark brown coloured • when they changed to yellow green complete loss of podophyllotoxin production was observed.
  • 12. Light grown callus cultures contained 3–4 times less podophyllotoxin in comparison to dark grown cultures.  The highest cellular accumulation of podophyllotoxin in suspension cultures was measured at day 15 during stationary phase of growth cycle followed by decrease in content.
  • 13. CALLUS AND CELL SUSPENSION CULTURES Podophyllotoxin production in callus cultures derived from rhizomes of Podophyllum peltatum was stimulated upon illumination. Cells cultured in media containing 4 mg L−1 Napthalene Acetic Acid accumulated 0.001–0.002% podophyllotoxin on dry weight basis. Feeding of 3mM coniferyl alcohol, dissolved in culture medium as β- cyclodextrin complex resulted in enhanced podophyllotoxin accumulation with a maximum of 0.012%.
  • 14. Use of transgenic hairy roots for the production of Podophyllotoxin • Genetically transformed hairy roots produced by infection of plants with Agrobacterium rhizogenes, a gram-negative soil bacterium, appear to be a promising tool for secondary metabolite production. • These hairy roots are unique in their genetic and biosynthetic stability and their fast growth offers an additional advantage. • These hairy roots are best experimental system for production of secondary metabolites • Podophyllotoxins are also produced from root cultures of Linum flavum ,cultures of Linum flavum produce 5 methoxy derivatives of podophyllotoxin (5 MPT). • Higher production (5–10 fold) of 5 MPT is reported from hairy roots than untransformed cell suspension cultures
  • 15. Bio-Transformation Approach • Recently the potential of biotransformation using cell cultures for the production of etoposide has been emphasized. • Etoposide is derived chemically from podophyllotoxin by two step conversion. • It has been demonstrated that a cell line of Podophyllum peltatum active in the biosynthesis of podophyllotoxin was able to maintain repeated biotransformation by oxidative coupling of the butanolide to the podophyllotoxin analouge. • It has been carried out in a bioreactor for a total of more than 15 cycles each of 24 h duration giving a yield of around 50%. • This result indicates the feasibility of a biotransformation route to podophyllotoxin using a chemically synthesized precursor
  • 16. Metabolic engineering considerations for the production of podophyllotoxin • Genetic engineering of metabolic pathways has recently been proved to be highly beneficial for the manipulation of secondary metabolite production. • Podophyllotoxin, which belongs to lignan group of compounds, is the product of Phenyl Propanoid Pathway (PPP).
  • 18. Metabolic Engineering • Recently in addition to CAD enzymes like Cinnamyl Co-enzyme Reductase(CCR) and Laccase have been isolated which has helped in the directed negative regulation of lignin biosynthesis. • These developments for the reduction of lignin synthesis may offer possibility for channeling precursor for the increased synthesis of lignans in the branched chain in the PPP biosynthetic pathway. • This diversion of biosynthetic pathway may offer the possibility to increase podophyllotoxin production.
  • 19. ESTIMATION OF PODOPHYLLOTOXIN • A simple, sensitive, specific, rapid and accurate high performance thin layer chromatographic (HPTLC) method has been developed for the quantification of podophyllotoxin • The method involved densitometric evaluation of podophyllotoxin after resolving it on silica gel plate using dichloromethane–methanol–formic acid (9.5:0.5:0.5 v/v/v) as the mobile phase. • The relationship between the concentration of standard solutions and the peak response (area) was linear within the concentration range of 150–2400 ng spot−1 for podophyllotoxin • The HPTLC method for the quantification of podophyllotoxin was found to be simple, precise, specific, sensitive and accurate which can be used for routine analysis and quality control of P. hexandrum and several formulations Instrumental precision was found to be 1.03–1.80 (% RSD)
  • 20. HPTLC INSTRUMENTATION AND EXPERIMENTAL CONDITIONS • The plates were developed in a 20 × 10 cm twin trough glass chamber (Camag, Switzerland). • A TLC scanner III was used for scanning the TLC plates. • Pre-coated silica gel aluminum plates 60F254 (E. Merck, Darmstadt, Germany) with a thickness of 0.2 mm were used for all determinations. • The plates were pre-washed with methanol and activated at 60 °C for 5 min prior to chromatography. • Five different volumes (0.3, 0.6, 1.2, 2.4, 4.8 μL) of standard solution of podophyllotoxin were applied on a 20 × 10 cm TLC plate for the preparation of the calibration curve of podophyllotoxin. • A constant application rate of 150 nL s−1 was employed for podophyllotoxin with a band width of 6.0mm for podophyllotoxin. • .
  • 21. HPTLC Instrumentation and Experimental Conditions • The scanning speed was employed at 20 mm s−1 for podophyllotoxin and the slit dimension was kept at 5.0 × 0.45 mm for podophyllotoxin. • Twenty mL of mobile phase consisting of dichloromethane-methanol-formic acid (9.5:0.5:0.5, v/v/v) was used per plate. • The optimized chamber saturation time for mobile phase was 15 min at room temperature (25 ± 2 °C) at relative humidity of 60 ± 5% RH. • The plates were developed and scanned within 10 min using densitometric scanner III in the absorbance mode at 292 nm for podophyllotoxin. • The source of radiation was deuterium lamp emitting a continuous radiation between 200 and 400 nm. The data obtained were analyzed by winCats software to get linear regression equation
  • 22. Rf value 0.66 HPTLC chromatogram of Podophyllotoxin (a) Standard and (b) Sample at 292 nm.
  • 23. UTILISATION OF PODOPHYLLOTOXIN(PPT) • 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. • Podophyllotoxin and its derivatives are used cathartic, purgative, antiviral agent, vesicant, antihelminthic, and antitumor agents. • Podophyllotoxin derived antitumor agents include etoposide and teniposide. • These drugs have been successfully used in therapy against numerous cancers including testicular, breast, pancreatic, lung, stomach, and ovarian cancers
  • 24. UTILISATION OF PODOPHYLLOTOXIN (PPT) • As a potent topical antiviral. • It is used for the treatment of HPV infections with external warts as well as molluscum contagisum infections. • PPT cream is highly effective with minimal side effects, which are typically limited to itching, irritation, and redness. • 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. • It can also be prescribed as a gel, as opposed to cream. • PPT is also sold under the names condyline and warticon.
  • 25. MARKETED PRODUCTS OF PODOPHYLLOTOXIN