ABSTRACT
Ethyl diazepane carboxylate catalyzes the oxy-Cope rearrangement of 4-hydroxy- and 4-alkoxy-1,5-hexadiene-2-carboxaldehydes via iminium ion activation. The resulting intermediate undergoes an intramolecular Michael reaction to furnish cyclopentane-containing products. The reaction proceeds with a range of substrates, including both cyclic and acyclic substrates, and tolerates substitution on the vinyl substituent. Substrates fused on a cycloalkane framework undergo net ring expansion/cyclopentannulation with a high degree of stereocontrol via chairlike transition states. The reaction extends iminium organocatalysis to the oxy-Cope rearrangement, embedded within a complexity-generating cascade transformation.
ABSTRACT
The combination of androgen receptor antagonists with histone deacetylase inhibitors (HDACi) has been shown to be more effective than antiandrogens alone in halting growth of prostate cancer cell lines. Here we have designed, synthesized and assessed a series of antiandrogen/HDACi hybrids by combining structural features of enzalutamide with either SAHA or entinostat. The hybrids are demonstrated to maintain bifunctionality using a fluorometric HDAC assay and a bioluminescence resonance energy transfer (BRET) antiandrogen assay. Antiproliferative assays showed that hybrids bearing o-aminoanilide-based HDACi motifs outperformed hydroxamic acid based HDACi's. The hybrids demonstrated selectivity for epithelial cell lines vs. stromal cell lines, suggesting a potentially useful therapeutic window.
