The first total synthesis of (+/-)-ingenol has been achieved. The key features of the synthesis include the use of a highly diastereoselective Michael reaction to fix the C-11 methyl stereochemistry and the incorporation of the dimethylcyclopropane via diastereoselective carbene addition to the Delta13,14 olefin. The intramolecular dioxenone photoaddition-fragmentation sequence leads to the establishment of the critical C-8/C-10 trans intrabridgehead stereochemistry, a central challenge in the synthesis of ingenanes. The completion of the synthesis proceeds using the C-6alpha hydroxymethyl group as the sole handle for oxidation of seven contiguous carbon centers.

Background: Human ubiquitin-like protein Ufm1 and its activating enzyme, Uba5, are involved in endoplasmic reticulum (ER) stress response. Results: The Uba5-Ufm1 conjugation pathway is characterized in both reconstituted systems and cellular settings. Conclusion: Uba5 activates Ufm1 via a distinct two-step mechanism. Significance: This study represents the first mechanistic characterization of Uba5, a homodimeric member of the E1 enzyme family.

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A screen for HDAC6 inhibitors identified acyl derivatives of 4-(aminomethyl)-N-hydroxybenzamide as potent leads with unexpected selectivity over the other subtypes. We designed and synthesized constrained heterocyclic analogues such as tetrahydroisoquinolines that show further enhanced HDAC6 selectivity and inhibitory activity in cellular assays. Selectivity may be attributed to the benzylic spacer more effectively accessing the wider channel of HDAC6 compared to other HDAC subtypes as well as hydrophobic capping groups interacting with the protein surface near the rim of the active site.

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