Synthesis of Novel Analogs of Belactosin A and Carfilzomib

Abstract

Belactosin A, a naturally occurring proteasome inhibitor with potent anti-tumor activity, was discovered in the late 1980’s. The key structural features of the natural product include a cyclopropane ring with a terminal β-lactone “serine trap”. Activity is conferred by acylation of the β-lactone with a threonine of the proteasome. Carfilzomib is a tetrapeptide epoxyketone, and an analog of epoxomicin with improved properties. In phase I and phase II clinical trials, carfilzomib exhibited higher selectivity, equal potency and less peripheral neuropathy than bortezomib and salinosporamide. Its activity is due to the formation of a highly stable six membered morpholine ring by the interaction between epoxyketone, free hydroxy and α-amino groups of the threonine.

Several syntheses of belactosin A and carfilzomib have been reported, however only a handful of analogs have been reported. An approach to the synthesis of novel hybrid analogs is reported here, with the synthesis of phenylalanine, leucine and valine cyclopropyl analogs of belactosin A with the epoxyketone of carfilzomib. Key steps in the synthetic route include a cyclopropanation and formation of an enone followed by epoxidation.