Identification of Highly Selective and Potent Histone Deacetylase 3 Inhibitors Using Click Chemistry-Based Combinatorial Fragment Assembly

To find histone deacetylase 3 (HDAC3)-selective inhibitors, a series of 504 candidates was assembled using “click chemistry”, by reacting nine alkynes bearing a zinc-binding group with 56 azide building blocks in the presence of Cu(I) catalyst. Screening of the 504-member triazole library against HDAC3 and other HDAC isozymes led to the identification of potent and selective HDAC3 inhibitors T247 and T326. These compounds showed potent HDAC3 inhibition with submicromolar IC₅₀s, whereas they did not strongly inhibit other isozymes. Compounds T247 and T326 also induced a dose-dependent selective increase of NF-κB acetylation in human colon cancer HCT116 cells, indicating selective inhibition of HDAC3 in the cells. In addition, these HDAC3-selective inhibitors induced growth inhibition of cancer cells, and activated HIV gene expression in latent HIV-infected cells. These findings indicate that HDAC3-selective inhibitors are promising candidates for anticancer drugs and antiviral agents. This work also suggests the usefulness of the click chemistry approach to find isozyme-selective HDAC inhibitors.     

Synthesis and odor description of both enantiomers of methyl 4,5-didehydrojasmonate, a component of jasmin absolute

Synthesis of both enantiomers of methyl 4,5-didehydrojasmonate (1, Delta(4,5)-MJA; >99.8% ee), a constituent of jasmin absolute, established the absolute configuration of the natural product, and their odor quality was evaluated. The fragrance of the natural (3S,7R)-enantiomer (a fresh natural, sweet floral fruity odor, reminiscent of Jasmin and Ylang Ylang flower, more intensive and tenacious) was superior to that of the unnatural (3R,7S)-enantiomer (a floral green odor with slight metallic green aspect, less intensive than the natural form) and the racemate (green-floral note, having weak and less volume than methyl jasmonate). Odor difference between natural and unnatural enantiomers of methyl jasmonate (2) is also reported.