Taxol Paclitaxel

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Taxol (Paclitaxel)

• Chalmers Natural Product Chemistry Selim NOURI
• April, 2003

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Overview of Taxol

• Potent Anticancer Natural Product
• Leukemia
• Solid Tumors
• Metastatic breast -48
• Ovary -30
• Brain
• Lung
• Isolated from Bark of Pacific Yew Tree (Taxus
  Brevifolia Nut)
• Supply Limited, (Bio)Synthetic Route Needed

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Outline

• Discovery
• Taxol activity
• Processing and Taxol design
• Pharmacokinetics
• Problems
• Analogs
• Future Prospects

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History/ Timeline of Taxol

• 1958 US National Cancer Institute initiates
  program to screen plants species for anticancer
  activity
• 1971 Dr. Monroe Wall and MC Wani of Research
  Triangle Institute identify the active ingredient
  in Pacific yew tree bark as Paclitaxel
• 1979 Paclitaxels unique mechanism of action is
  discovered
• 1983 Research triangle sponsors phase I
  clinical trials of paclitaxel

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Timeline (cont)

• 1985 NCI begins phase II trials of Paclitaxel
• 1989 NCI issues an open invitation to
  pharmaceutical companies to compete for the right
  to be its commercial development partner for the
  drug
• 1991 Bristol Myers Squibb Company is selected
  by NCI to be the commercial partner in developing
  Taxol injections

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Taxol activitystabilizing microtubules

• Microtubules are conveyer belts inside the cells
• Important role in mitosis (FLEX)

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Pharmacokinetics
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By binding to tubulin and causing the protein to
lose its flexibility, taxol prevents a cell from
dividing.
Better knowledge of tubulin-taxol interaction
may lead to more effective anti-cancer drug, that
interacts only with the tubulin of cancerous
cells
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Taxol processing.

• Harvesting drying storage
• Extraction purification SCFE, HPLC

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Retro Synthesis of Taxol
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Taxol Skeleton (tricyclic diterpene)

• Oxetane Ring crucial for maintaining activity
• Eight member ring provides molecule tubulin
  depolymerization properties
• Removal C10 acetyl group no effect
• C2-0 benzoyl group removal causes reduction to
  activity

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Taxol SAR
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Taxol Semi-Synthesis
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Pharmacokinetics

• Administered through Intravenous Injection
• Highly Lipophilic
• Insoluble in water (bioavailability..)
• gt Taxotere more water soluble.

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Problems

• Low Solubility in Water
• Debilitating Side Effects
• Powerless against some cancers
• Colon
• Devising Synthetic version is difficult b/c of
  chemical complexity
• When Taxol fails to kill off all cancerous cells,
  a tumor can grow back with resistant mutations

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Side Effects

• Temporary Reduction in bone marrow function
• Mouth Sores and Ulcers
• Diarrhoea
• Hair Loss
• Low Blood Pressure

• Aching or Paining in joints and muscles
• Skin Changes
• Numbness of tingling in hands and feet
• Headaches
• Allergic Reactions
• Nausea and Vomiting

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Analogs

• Taxotere
• Prodrugs
• Poly(ethylene glycol) -(-CH2 CH2 O-)-

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Future Prospects

• Epothilones - Taxol-like activity
• - more soluble in water
  
• - higher activity and
  are more easily available (i.e. from a cellulose
  degrading bacterium).
• Orally administered taxanes instead of hour long
  IV doses

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Taxol is depicted to the top left, and epothilone
to the top right. The bottom half of the figure
shows a proposed alignment between Taxol and
epothilone.
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Questions?!