Indoles, both naturally occurring and synthetic, exhibit wide-ranging biological activity. Unusual and complex molecular architectures occur among their natural derivatives. As a result, this important ring system continues to attract attention from the international chemical community, and new methodologies for the construction of this ever relevant heteroaromatic ring continue to be developed.Unfortunately, many methods frequently start from ortho-substituted anilines, thereby greatly restricting the availability of starting materials. A more general approach would start from a mono-functionalized arene such as an aniline or halobenzene, followed by cyclization with C-C or C-N bond formation to an unactivated C-H bond. Such methods are the subject of this perspective.

Objective. To characterize the role of histone deacetylase (HDAC) activity in rheumatoid arthritis (RA) and to evaluate the effects of MI192, a novel HDAC-3-selective inhibitor, compared with the established nonselective HDAC inhibitor trichostatin A (TSA), on proinflammatory cytokine production.Methods. Activity of HDAC and histone acetyltransferase was measured in peripheral blood mononuclear cells (PBMCs) from RA patients by spectrophotometric assay, prior to and after 12 weeks of etanercept therapy. The effects of HDAC inhibitor treatment on cytokine production in both RA and healthy PBMCs were assessed by enzyme-linked immunosorbent assay.Results. RA PBMCs exhibited significantly increased HDAC activity (P ‫؍‬ 0.007) compared to PBMCs from healthy individuals, and the increase was unaltered after 12 weeks of etanercept therapy. TSA was a potent inhibitor of tumor necrosis factor (TNF) and interleukin-6 (IL-6) production in both RA and healthy PBMCs and of interferon-␥ (IFN␥) production in healthy PBMCs; IFN␥ was not produced by RA PBMCs. MI192 inhibited TNF production at high concentrations and dose-dependently inhibited IL-6 in RA PBMCs but not healthy PBMCs, across a dose range of 10 M-5 nM.Conclusion. HDAC activity is dysregulated in RA PBMCs and is a potential target for therapeutic intervention, as it is not affected by conventional anti-TNF treatment with etanercept. Both the selective and the nonselective HDAC inhibitors (MI192 and TSA, respectively) were found to regulate cytokine production from PBMCs, but their effects were cell type and compound specific. HDAC inhibitors have potential in the treatment of RA, and HDAC-selective inhibition may improve the therapeutic margin of safety; however, further clinical characterization and evaluation for adverse effects is needed.

No abstract

A Cu(II)-mediated synthesis of indolequinones from the corresponding bromoquinones and enamines is reported. The key oxidative cyclization proceeds in good yield for a broad range of substrates and can be performed on a multigram scale, allowing access to biologically interesting structures.

A series of benzofuranquinones, analogues of the marine metabolite annulin A, has been synthesized and evaluated as inhibitors of human indoleamine 2,3-dioxygenase (IDO). The synthesis was carried out by copper(II)-mediated reaction of bromobenzoquinones with 1,3-dicarbonyl compounds followed by functional group interconversions. The most potent compounds were 5-methoxy-2-methylbenzofuranquinones containing a CH2OR group at position-3 with IC50 ~ 0.2 mM. The corresponding hydroquinones were inactive. Compounds based on the benzimidazolequinone framework are also active IDO inhibitors. The quinones do not generate significant levels of oxidative stress at concentrations that inhibit IDO.