SOLVENT-DEPENDENT AND CONCENTRATION-DEPENDENT MOLECULAR-INTERACTIONS OF TAXOL (PACLITAXEL)

Taxol (paclitaxel) is a promising anticancer agent that has been appro ved for the treatment of ovarian cancer and is under investigation for the therapy of other tumors. Paclitaxel is poorly soluble in water, a nd information on its physical behavior in hydrophilic and hydrophobic environments is limited. Circular dichroism (CD) and nuclear magnetic resonance spectroscopy were used to investigate the effect of solvent and drug concentration on the solution conformation of paclitaxel. CD is sensitive to paclitaxel's environment, owing to the presence of ef fective chromophores in the vicinity of several chiral centers. It was found that (i) the conformation of the paclitaxel side chain depends on the polarity of the solvent and (ii) paclitaxel has a tendency to u ndergo concentration-dependent aggregation in solvents such as chlorof orm. To account for the observations, a model is proposed in which pac litaxel molecules are held together in stacks by intermolecular hydrog en bonds involving all four exchangeable protons. Intermolecular inter actions and self-association of paclitaxel may have impact not only on the physical stability of the drug in existing formulations or invest igational vehicles but also on the effect of paclitaxel in the stabili zation of cellular microtubules.