- Palladium-mediated N-arylation of heterocyclic diamines: Insights into the origin of an unusual chemoselectivity
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The chemoselectivity of the palladium-mediated reaction of bromobenzene with various heterocyclic diamines was studied. Whatever the ligand used, 3-aminopyrrolidine underwent arylation of the secondary amine function (> 82%), whereas the more flexible 3-aminoazepinine was arylated on its primary function (>70%). The ratio "arylation of primary amine versus arylation of secondary amine" of 3-aminopiperidine with bromobenzene varied from 90:10 (BINAP, electron-enriched and hindered biphenyls L2 or L3) to 32:68 with the Josiphos-type ligand L10. The same trend was observed when 4-aminopiperidine was used (82:18 with L2 and 17:83 with L10). This selectivity can be tuned by the choice of aryl halide partners having different steric and electronic properties. A cooperative effect of both nitrogens of diamines during the reaction was deduced from competitive experiments. Finally, 13C and 31P NMR experiments, carried out with 3-aminopyrrolidine at room temperature, support a fast coordination of the primary amine to the metal. Indeed, a palladium complex resulting from the unusual displacement of one phosphane group of the intermediate ArPdX(BINAP) by the primary amino group was characterized.
- Cabello-Sanchez, Noemi,Jean, Ludovic,Maddaluno, Jacques,Lasne, Marie-Claire,Rouden, Jacques
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- Potent small molecule Hedgehog agonists induce VEGF expression in vitro
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Here, we describe the synthesis, SAR studies as well as biological investigations of the known Hedgehog signaling agonist SAG and a small library of its analogues. The SAG and its derivatives were analyzed for their potency to activate the expression of the Hh target gene Gli1 in a reporter gene assay. By analyzing SAR important molecular descriptors for Gli1 activation have been identified. SAG as well as compound 10c proven to be potent activators of VEGF expression in cultivated dermal fibroblasts. Importantly and in contrast to SAG, derivative 10c displayed no toxicity in concentrations up to 250 μm.
- Seifert, Katrin,Buettner, Anita,Rigol, Stephan,Eilert, Nicole,Giannis, Athanassios,Wandel, Elke
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p. 6465 - 6481,17
(2012/12/11)
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- Synthesis and SAR of conformationally restricted inhibitors of soluble epoxide hydrolase
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A series of conformationally restricted inhibitors of human soluble epoxide hydrolase (sEH) has been developed. Inhibition potency of the described compounds ranges from 4.2 μM to 1.1 nM against recombinant sEH. N-(1-Acetylpiperidin-4-yl)-N′-(adamant-1-yl) urea (5a) was found to be a potent inhibitor (IC50 = 7.0 nM) that was also orally bioavailable in canines.
- Jones, Paul D.,Tsai, Hsing-Ju,Do, Zung N.,Morisseau, Christophe,Hammock, Bruce D.
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p. 5212 - 5216
(2008/02/03)
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