The selectivity of histone deacetylase inhibitors (HDACis) is greatly impacted by the zinc binding groups. In an effort to search for novel zinc binding groups, we applied a parallel medicinal chemistry (PMC) strategy to quickly synthesize substituted benzamide libraries. We discovered a series containing 2-substituted benzamides as the zinc binding group which afforded highly selective and potent HDAC3 inhibitors, exemplified by compound 16 with a 2-methylthiobenzamide. Compound 16 inhibited HDAC3 with an IC 50 of 30 nM and with unprecedented selectivity of >300-fold over all other HDAC isoforms. Interestingly, a subtle change of the 2-methylthio to a 2-hydroxy benzamide in 20 retains HDAC3 potency but loses all selectivity over HDAC 1 and 2. This significant difference in selectivity was rationalized by X-ray crystal structures of HDACis 16 and 20 bound to HDAC2, revealing different binding modes to the catalytic zinc ion. This series of HDAC3 selective inhibitors served as tool compounds for investigating the minimal set of HDAC isoforms that must be inhibited for the HIV latency activation in a Jurkat 2C4 cell model and potentially as leads for selective HDAC3 inhibitors for other indications.

A combinatorial approach revealed the highly selective binding of the dipeptides L‐Phe‐D‐Pro and D‐Phe‐L‐Pro to β‐cyclodextrin. NMR spectroscopy and molecular modeling provide a picture of the possible binding mode and an explanation of why those specific dipeptides were selected from the tripeptide library.

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is implicated in the etiology of metabolic syndrome. We previously showed that pharmacological inhibition of 11β-HSD1 ameliorated multiple facets of metabolic syndrome and attenuated atherosclerosis in ApoE-/- mice. However, the molecular mechanism underlying the atheroprotective effect was not clear. In this study, we tested whether and how 11β-HSD1 inhibition affects vascular inflammation, a major culprit for atherosclerosis and its associated complications. ApoE-/- mice were treated with an 11β-HSD1 inhibitor for various periods of time. Plasma lipids and aortic cholesterol accumulation were quantified. Several microarray studies were carried out to examine the effect of 11β-HSD1 inhibition on gene expression in atherosclerotic tissues. Our data suggest 11β-HSD1 inhibition can directly modulate atherosclerotic plaques and attenuate atherosclerosis independently of lipid lowering effects. We identified immune response genes as the category of mRNA most significantly suppressed by 11β-HSD1 inhibition. This anti-inflammatory effect was further confirmed in plaque macrophages and smooth muscle cells procured by laser capture microdissection. These findings in the vascular wall were corroborated by reduction in circulating MCP1 levels after 11β-HSD1 inhibition. Taken together, our data suggest 11β-HSD1 inhibition regulates proinflammatory gene expression in atherosclerotic tissues of ApoE-/- mice, and this effect may contribute to the attenuation of atherosclerosis in these animals.

Many biological recognition events involve extensive interactions between macromolecules. Strategies to design compounds that mimic large peptides or other elements of secondary structure could be useful for blocking interactions between large surfaces. In this paper, the use of oligosaccharides as scaffolds for the design of peptidomimetics is addressed. A functionalized oligosaccharide modeled after a basic region peptide helix has been designed and synthesized. This oligosaccharide binds to duplex DNA with micromolar affinity. The mode of binding has been established by 2D NMR, and shows that the oligosaccharide binds DNA in the minor groove with one surface of the oligosaccharide contacting the floor of the DNA.

An integrated workflow has been established that enables the synthesis, purification, and subsequent biological testing of compound libraries on a microgram scale. This approach utilizes mass directed preparative HPLC in conjunction with charged aerosol detection (CAD) to generate solutions of investigational compounds at high purity and standardized concentrations, facilitating high fidelity biological testing. This new workflow successfully delivered libraries of histone deacetylase (HDAC) inhibitors that afforded biological data consistent with that obtained from standard scale parallel medicinal chemistry techniques. The advantages of this new approach to library synthesis include greatly reduced material requirements and amenability to high-throughput experimentation.