A novel bioinspired iron-catalyzed oxidative cross-coupling reaction between phenols and conjugated alkenes was developed. This method enables the direct coupling of phenols with styrene, α-alkyl- and α-arylstyrenes, β-alkyl styrenes, and stilbenes, thereby providing a new strategy for the preparation of the pharmacologically important 2,3-dihydrobenzofuran motif. In addition, this study revealed that under a different set of conditions an oxidative/addition dearomatization reaction of 1,1'-bi-2-naphthol (BINOL) with styrene can take place.

A chemo-, regio-, and stereoselective FeCl(3)/1,10-phenanthroline-catalyzed cross dehydrogenative coupling (CDC) reaction between phenols and α-substituted β-ketoesters was developed. The reaction creates a new quaternary carbon center within a polycyclic hemiacetal or polycyclic spirolactone architecture. The applicability of the new method to the synthesis of natural products was demonstrated by a possible biomimetic synthesis of the lachnanthospirone core.

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Lysine deacetylases (KDACs) are enzymes that catalyze the hydrolysis of acyl groups from acyl-lysine residues. The recent identification of thousands of putative acylation sites, including specific acetylation sites, created an urgent need for biochemical methodologies aimed at better characterizing KDAC-substrate specificity and evaluating KDACs activity. To address this need, we utilized genetic code expansion technology to coexpress site-specifically acylated substrates with mammalian KDACs, and study substrate recognition and deacylase activity in live Escherichia coli. In this system the bacterial cell serves as a “biological test tube” in which the incubation of a single mammalian KDAC and a potential peptide or full-length acylated substrate transpires. We report novel deacetylation activities of Zn2+-dependent deacetylases and sirtuins in bacteria. We also measure the deacylation of propionyl-, butyryl-, and crotonyl-lysine, as well as novel deacetylation of Lys310-acetylated RelA by SIRT3, SIRT5, SIRT6, and HDAC8. This study highlights the importance of native interactions to KDAC-substrate recognition and deacylase activity.

Therapeutics with activity specifically at the inflamed sites throughout the gastrointestinal tract (GIT) would be a major advance in our therapeutic approach to inflammatory bowel disease (IBD). We aimed to develop the prodrug approach that can allow such site-specific drug delivery. Currently, using cyclosporine as a drug of choice in IBD is limited to the most severe cases due to substantial systemic toxicities and narrow therapeutic index of this drug. Previously, we synthesized a series of a phospholipid-linker-cyclosporine (PLC) prodrugs designed to exploit the overexpression of phospholipase A2 (PLA2) in the inflamed intestinal tissues, as the prodrug-activating enzyme. Nevertheless, the extent and rate of prodrug activation differed significantly. In this study we applied in-vitro and modern in-silico tools based on molecular dynamics (MD) simulation, to gain insight into the dynamics and mechanisms of the PLC prodrug activation. We aimed to elucidate the reason for the significant activation change between different linker lengths in our prodrug design. Our work reveals that the PLC conjugate with the 12-carbon linker length yields the optimal prodrug activation by PLA2 in comparison to shorter linker length (6-carbons). This optimized length efficiently allows cyclosporine to be released from the prodrug to the active pocket of PLA2. This newly developed mechanistic approach, presented in this study, can be applied for future prodrug optimization to accomplish optimal prodrug activation and drug targeting in various conditions that include overexpression of PLA2.