Chemoselective [3 + 2] annulation of oxime acetate with 2-aryl-3-ethoxycarbonyl-pyrroline-4,5-dione: an entry to pyrrolo[2,3-b]pyrrole derivatives.

A novel chemoselective [3 + 2] annulation reaction of easily accessible ketoxime acetate with 2-aryl-3-ethoxycarbonyl pyrroline-4,5-dione has been developed for the synthesis of unknown pyrrolo[2,3-b]pyrrole frameworks. This method involves copper-mediated N-O bond cleavage followed by the formation of carbon-carbon and carbon-nitrogen bonds. This operationally simple protocol provides broader functional group compatibility and good yields.

Access to pyrrolo[2,1-a]isoindolediones from oxime acetates and ninhydrin via Cu(i)-mediated domino annulations.

A copper-mediated domino condensation reaction of readily accessible oxime acetates with ninhydrin is reported to afford pyrrolo[2,1-a]isoindolediones via new C-C & C-N bond formations. A wide range of oxime acetates were shown to generally participate in the reaction to produce the condensed products in excellent yields. The necessary control experiments were performed and the mechanism is proposed to involve sequentially the formation of iminium radical via Cu-mediated N-O bond cleavage of oxime acetates, addition of the radical to ninhydrin and rearrangement via ring expansion.

Oxidative Aza-Annulation of Enynyl Azides to 2-Keto/Formyl-1H-pyrroles.

A method for the construction of pyrroles bearing a 2-keto or formyl group through the intramolecular oxidative aza-annulation of enynyl azides is reported for the first time. It involves a sequential carbon-nitrogen/carbon-oxygen bond formations, and the combination of AuCl3 with AgSbF6 was identified as a suitable reagent system to promote the present reaction. The required enynyl azides are readily prepared from Morita-Baylis-Hillman (MBH) acetates of acetylenic aldehydes.

Novel, Brain-Permeable, Cross-Species Benzothiazole Inhibitors of Microsomal Prostaglandin E Synthase-1 (mPGES-1) Dampen Neuroinflammation In Vitro and In Vivo.

Microsomal prostaglandin E synthase-1 (mPGES-1) is an inducible enzyme of the cyclooxygenase (COX) cascade that generates prostaglandin E2 (PGE2) during inflammatory conditions. PGE2 is known to be a potent immune signaling molecule that mediates both peripheral and central inflammations. Inhibition of mPGES-1, rather than COX, may overcome the cardiovascular side effects associated with long-term COX inhibition by providing a more specific strategy to target inflammation. However, mPGES-1 inhibitor development is hampered by the large differences in cross-species activity due to the structural differences between the human and murine mPGES-1. Here, we report that our thiazole-based mPGES-1 inhibitors, compounds 11 (UT-11) and 19 derived from two novel scaffolds, were able to suppress PGE2 production in human (SK-N-AS) and murine (BV2) cells. The IC50 values of inhibiting PGE2 production in human and murine cells were 0.10 and 2.00 µM for UT-11 and 0.43 and 1.55 µM for compound 19, respectively. Based on in vitro and in vivo pharmacokinetic data, we selected UT-11 for evaluation in a lipopolysaccharide (LPS)-induced inflammation model. We found that our compound significantly suppressed proinflammatory cytokines and chemokines in the hippocampus but not in the kidney. Taken together, we demonstrated the potential of UT-11 in treating neuroinflammatory conditions, including epilepsy and stroke, and warrant further optimization.