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Taxol (Molecule of the Month for August 1996)

Taxol, a potent anticancer natural product (with activity against a number of leukeamias and solid tumours in the breast, ovary, brain, and lung in humans) has stimulated an intense research effort over recent years. Taxol was isolated from the bark of the pacific yew ( Taxus brevifolia Nutt ) in 1971 and the structure elucidated by Wani and Wall. The initial biological activity was related to the microtubule-destabilizing properties of the vinca alkaloids. However, research by Horwitz et al 4 indicated that the biological activity was in fact unique. It was shown to have a complementary effect: i.e. binding to polymerised tublin, stabilising it against disassembly and consequently inhibiting mitosis.

Phase I clinical trails began in 1983 with Taxol in short supply. Research efforts intensified on the synthesis and a number of groups began their approaches. It concluded after a decade in the total synthesis by Holton and Nicolaou simultaneously. However the total synthesis was preceded by the more efficient semisynthesis of Taxol from baccatin III (2) which enabled compounds to be administered in clinical tests. As a result, the semisynthesis approaches have recently been utilised in the synthesis of analogues in order to (i) understand the molecular basis of its activity, (ii) synthesise a more potent Taxol analogue with higher selectivity for tumour cells, (iii) synthesise a molecule with limited complexity but similar mechanism of action of Taxol.

The structure activity relationships of taxol has been studied by a multitude of researchers. The molecule can divided into two parts; the side chain and taxol skeleton. Side Chain The side chain of taxol is critical for maintaining activity. The structure activity of the side has been studied by Potier and Swindell. The studies have revealed the following features:

  • Protection of the C2' hydroxyl group as a ester results in loss of activity in terms of microtublin stabilization but not in cytotoxicity.
  • The C3' amide-acyl group is critical but may be aromatic or alkyl in nature.
  • The C3' bound nitrogen can be replaced by a oxygen atom without loss of activity.
  • The C3' aryl group is needed, replacement by a methyl group reduces the activity 19-fold.
Taxol Skeleton Taxol consists of several rings: a four membered ring and a six membered ring and eight membered ring and peripheral functionalities. Modification of the taxol skeleton and elucidation of its structure activity have lead to the following features:
  • The oxetane ring is crucial for maintaining the activity, ring opening leads to a dramatic decrease in bioactivity.
  • Contraction of the eight membered ring to a seven membered ring still provides the molecule with tublin depolymerization properties.
  • Removal of the C10 acetyl group does not have any effect on the activity.
  • C2-O-benzoyl group removal causes a drastic reduction to activity.

  • Formal Chemical Name (IUPAC)

    Picture of Taxol

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    Taxol structure
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    Picture of Taxol

    Update by Karl Harrison
    (Molecule of the Month for August 1996 )