A series of conformationally constrained paclitaxel derivatives have been synthesized. These molecules are covalently linked between the C-3' aromatic ring and C-4 acetyl group positions on the parent molecule. It was determined that linking the C-4 to an ortho-carbon on the C-3' phenyl greatly enhanced the activity of the ligand over its unconstrained counterpart. A general trend has emerged showing that the macrocyclic taxanes are more effective promoters of tubulin assembly than would be predicted based on their affinities for microtubules. The taxane derivatives with a three carbon tether exhibited highest affinity for microtubules and were the most effective promoters of tubulin assembly. A more detailed investigation revealed that these bridged taxanes were efficient in promoting the assembly of GDP-tubulin under low temperatures conditions and absence of Mg2+ ions in 0.10 M PIPES. Thus the bridged macrocyclic taxanes with a three atom tether promote tubulin assembly more effectively than paclitaxel. Supported by NIH grant CA-69571 and NSF grant DBI-0321046.