In Vitro and In Vivo Osteogenic Activity of Largazole.

Due to their capability of modifying chromatin structure and thereby regulating gene transcription, histone deacetylases (HDACs) have been reported to play important roles in osteogenesis and considered a promising potential therapeutic target for bone diseases, including osteoporosis. We showed that the novel marine-derived HDAC inhibitor largazole exhibits in vitro and in vivo osteogenic activity. Largazole significantly induced the expression of ALP and OPN.

Enantioselective dichlorination of allylic alcohols.

The development of an enantioselective allylic alcohol dichlorination catalyzed by dimeric cinchona alkaloid derivatives and employing aryl iododichlorides as chlorine sources is reported. Reaction optimization, exploration of the substrate scope, and a model for stereoinduction are presented.

Characterization of Fe(III) sequestration by an analog of the cytotoxic siderophore brasilibactin A: implications for the iron transport mechanism in mycobacteria.

Mycobacteria such as M. tuberculosis represent a significant health concern throughout much of the developing world. In mycobacteria and other pathogenic bacteria, an important virulence factor is the ability of the bacterium to obtain iron from its host.

Stereoselective synthesis of 2,6-cis- and 2,6-trans-piperidines through organocatalytic aza-Michael reactions: a facile synthesis of (+)-myrtine and (-)-epimyrtine.

Both 2,6-cis- and 2,6-trans-piperidines were prepared from common substrates through organocatalytic aza-Michael reactions promoted by the gem-disubstituent effect in conjunction with dithiane coupling reactions. The organocatalytic aza-Michael reaction enabled a facile synthesis of (+)-myrtine and (-)-epimyrtine from a common substrate.

Anticolon cancer activity of largazole, a marine-derived tunable histone deacetylase inhibitor.

Histone deacetylases (HDACs) are validated targets for anticancer therapy as attested by the approval of suberoylanilide hydroxamic acid (SAHA) and romidepsin (FK228) for treating cutaneous T cell lymphoma. We recently described the bioassay-guided isolation, structure determination, synthesis, and target identification of largazole, a marine-derived antiproliferative natural product that is a prodrug that releases a potent HDAC inhibitor, largazole thiol. Here, we characterize the anticancer activity of largazole by using in vitro and in vivo cancer models.

Synthesis and activity of largazole analogues with linker and macrocycle modification.

To characterize largazole's structural requirements for histone deacetylase (HDAC) inhibitory and antiproliferative activities, a series of analogues with modifications to the side chain or 16-membered macrocycle were prepared and biologically evaluated. Structure-activity relationships suggested that the four-atom linker between the macrocycle and octanoyl group in the side chain and the (S)-configuration at the C17 position are critical to repression of HDAC activity. However, the valine residue in the macrocycle can be replaced with alanine without significant loss of activity.