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TAXOL

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2. Biological Mechanism of Action



Initially, the anticancer activity of taxol was attributed to the general microtubule destabilising properties of the vinca alkaloids6.   However, in 1979 Dr. S.B. Horwitz working with a number of other collaborators at the Albert Einstein Medical College disclosed their findings on the interaction of taxol with microtubules5.  Horwitz's research indicated that the initial hypothesis concerning taxol's activity was incorrect and that taxol's method of action was in fact unique.  Their work showed that taxol bound to polymerised tublin promoting microtubule formation and microtubule stabilisation against disassembly and hence inhibiting mitosis and therefore cancer growth.

Further research led to the narrowing down of taxol's binding domain to a 31 amino acid sequence.  This peptide was then probed using multidimensional NMR spectroscopy and electron microscopy to yield a picture of the site where taxol is thought to bind (2).

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2: taxol binding site
Click here for Hi-Res version

"T" marks the approximate position of the taxol binding site, which is shown at a resolution of about 6.5 angstroms.  This discovery generated a great deal of interest in taxol and was the catalyst for a great deal of research into it's structure with the aim of developing a full stereoselective synthesis.

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