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5. Current Taxol Analogues

A number of groups are currently working on the production of a range of taxol analogues that although similar in structure to the natural product taxol are easier to make synthetically and/or have increased activity against cancer.  Extraction of leaves and stems of Taxus chinensis has now yielded a further nine structures similar in structure to that of taxol but possessing enhanced activity with less side effects.   Two are taxchins, for example taxchin A (12), and contain the bridging gem-dimethyl group that is common in this class of structure. While the remainder (taxchinins D, E, G-K; for example (13)) have a simple fused ring system24.

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12: Taxchin A

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13: Taxchinin D

These molecules are, however, as difficult to synthesise as taxol and so really on present an alternative natural source for the drug without solving the problem of procuring enough supplies.

One solution is docetaxel (Taxotere®) (14) that was the result of a collaborative research project between Rhône-Poulenc Rorer and the French Centre National de la Recherche Scientifique in the late 1980's25.   Taxotere is a synthetic form of taxol that has a hydroxyl group in place of acetoyl group at position 10 on the taxol B ring and an N-tert-butoxycarbonyl group instead of the N-benzoyl group on the taxol side chain. Preliminary trials in 1990 indicated high activity against metastatic cancer.  Phase II studies were started in 1992 to investigate its safety and efficacy in a variety of solid tumours, including locally advanced or metastatic breast and non-small cell lung (NSCL) cancers. By the end of 1994, more than 2600 patients had been enrolled in Phase I, II, and III clinical studies worldwide26.

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14: Docetaxel (Taxotere)

Docetaxel works via a different method to that of taxol, disrupting the microtubular network in cells that is essential for mitosis to occur as well as effecting the normal microtubule-regulated cellular activities.  This mechanism of action results in less severe side effects than taxol.

Taxotere synthesis from the 10-deacetylbaccatin III precursor, found in the needles of the European yew tree (taxus baccata), is easier than the synthesis of taxol and so this molecule represents a significant therapeutic advance27.   The total synthesis from commonly available starting materials is, however, too involved to allow it's synthesis on a large scale.

The search for simpler analogues that are easier to synthesise from bulk chemicals is therefore still ongoing with a number of groups still contributing to the growing wealth of knowledge concerning these compounds.