Synthesis and Evaluation of a Linkable Functional Group-Equipped Analogue of the Epothilones

An approach to the validation of a linker strategy for the epothilone family of microtubule-stabilizing agents is reported. An analogue of epothilone B in which the C(6) methyl group has been replaced with a 4-azidobutyl group has been prepared by total chemical synthesis, and amides derived from the azido group have been shown to retain the activity of the parent compound. These results set the stage for an evaluation of the potential of the epothilones to serve as the drug component of antibody-drug conjugates and Other selective tumor cell-targeting conjugates.

Epothilones; antibody−drug conjugates; linker; methyl extension; microtubules.