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TAXOL

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3. Structure and Activity

In order to better understand the mechanism by which taxol operates and hence find possible analogues of taxol, such as DocetaxelŽ, that have the same anticancer properties but which might prove easier to synthesise, a number of structure activity relationships have been studied by many different researchers.  The results of these studies are summarised below:		 taxol1.gif (1815 bytes)

The molecule taxol.

The structure of taxol, for ease of analysis, can be divided into two parts;  the taxol skeleton and the side chain. .  In the following paragraphs the structure of these two parts is described in detail and the effects that each functional group has on taxol's activity is discussed.

1. The Taxol Skeleton
Many people have studied the main skeleton of taxol.  The taxol backbone consists of an eight membered ring , a six membered ring and a four membered ring .  Attached to these rings are several functional groups including and OH group, two benzoyl groups,  an acetyl group and an oxetane ring.   Modification of the taxol skeleton followed by analysis of the resulting molecules structure have resulted in the following findings concerning the 4-10-6 skeleton of taxol:

  • Removal of the C2-O-benzoyl group results in a large reduction of activity.
  • Reducing the size of the eight membered ring to a seven membered ring still provides the molecule with tublin depolymerization properties.
  • Removing the C10 acetyl group does not effect the activity.
  • The oxetane ring is crucial for maintaining the activity.  Opening of this ring leads to a large decrease in reactivity.

2. The Side Chain
The structure and activity of the side chain of taxol has been studied in depth by Potier7 and Swindell8. Their research showed that the side chain is critical for maintaining taxol's activity.  Their work revealed the following properties of the side chain:

  • The C3' bound nitrogen can be replaced with an oxygen atom without jeopardising taxol's activity.
  • The C3' aryl group is needed in order to maintain activity.  Replacement by a methyl group reduces the activity by over 19 fold.
  • The C2' hydroxyl group is also necessary for maintaining taxol's activity.   Protection as an ester results in a loss of activity in terms of microtublin stabilisation but not in its cytotoxicity.
  • The C3' amide-acyl group group is critical but may be replaced with  an arromatic or alkyl group without jeopardising the reactivity.

A greater knowledge of the mechanism by which taxol operates and what parts of it's structure are essential to maintaining the anti cancer activity have provided scientists with the information necessary to prepare simpler alternatives while still maintaining the anti cancer properties of the taxol  molecule.

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