Design, synthesis and biological evaluation of novel paclitaxel analogs for brain delivery

Paclitaxel, a cytotoxic agent derived from Taxus brevifolia, is an effective agent for the treatment of a variety of cancers. However, the continued evaluation of new analogues is important, because drug resistance has developed, and paclitaxel, like many other anticancer agents, does not cross the blood-brain barrier (BBB). Active efflux by P-glycoprotein (Pgp) is believed to be responsible for all of these limitations.; In order to provide an efficient, reliable way to synthesize paclitaxel analogs, a systematic study of the kinetic resolution between racemic beta-lactams and 7-TES-baccatin III was carried out. It was found that the size of either the silylether protecting groups on the 3-hydroxy moiety or the 4-substituents of the beta-lactam had an important influence on the diastereoselectivity of the resolution. High diastereoselectivity can be obtained either by using sterically demanding C3-hydroxy protecting groups or C4 substituents.; Based on our hypothesis that the deletion of recognition elements on paclitaxel can reduce the interaction with Pgp, three deoxypaclitaxel analogs were synthesized and evaluated in tubulin assembly, cytotoxicity, and in vitro BBB permeability assays. These analogs showed similar or superior activity compared with paclitaxel in cytotoxicity/tubulin stabilization ability. Most importantly, our original hypothesis, that the removal of Pgp recognition elements could decrease the strength for Pgp binding was verified, because rhodamine 123 uptake was clearly reduced for the 10-deacetoxy and 10-deacetoxy-7-deoxy paclitaxel analogs in BMEC's.; Tx-67, a semi-synthetic paclitaxel analog developed in the Georg group, showed significantly decreased interaction with Pgp in vitro and in situ. Analogs of Tx-67 were synthesized that showed comparable cytotoxicity to paclitaxel. In a rhodamine assay, none of the carboxylic acid analogs had apparent interactions with Pgp. Furthermore, none of these analogs activated PXR indicating that chemical modification of paclitaxel could provide an approach to reduce PXR activation.; Multiple modifications at the C3', C7, and C10 positions were carried out to investigate the structure-Pgp efflux relationships of paclitaxel analogs. Most of these analogs showed similar or increased cytotoxicity compared to paclitaxel. Furthermore, attachment of a carboxylic acid moiety at the C10 position significantly decreases Pgp affinity.