Functionalized pyrrolidines as alpha-mannosidase inhibitors and growth inhibitors of human glioblastoma and melanoma cells

New substituted pyrrolidine-3,4-diol derivatives were prepared from D-(-)- and L-(+)-phenyl glycinol. The influence of the configuration and the substitution of the lateral side chain of these derivatives on the inhibition of 25 commercial glycosidases were determined. (2R,3R,4S)-2-({[(1R)-2-Hydroxy-1-phenylethyl]amino}methyl)pyrrolidine-3,4-diol ((+)-7a) was a potent and selective inhibitor of jack bean alpha-mannosidase (Ki = 135 nM). However, when evaluated on human tumor cells, 7a, and the reference compound swainsonine, did not efficiently inhibit the growth of glioblastoma cells. Further derivatization of the hydroxyl group with lipophilic groups to increase bioavailability improved their growth inhibitory properties for human glioblastoma and melanoma cells. In particular the 4-bromobenzoyl derivative 26 demonstrated high efficacy for human tumor cells whereas primary human fibroblasts were less sensitive to 26. Therefore functionalized pyrrolidines have the potential to inhibit the growth of tumor cells and display selectivity for tumor cells compared to normal cells

Synthesis of 5-azaindoles via a cycloaddition reaction between nitriles and donor-acceptor cyclopropanes.

A new method for the synthesis of 5-azaindole derivatives is reported. A [3+2] dipolar cycloaddition between nitriles and a 3,4-cyclopropanopiperidine followed by SeO(2) oxidation affords the target compounds in moderate to excellent yields. The divergent nature and cost effectiveness of this method makes it very suitable for combinatorial applications in the pharmaceutical industry

Straightforward synthesis of 2-acetyl-substituted benzo[b] tiophenes

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HMF in multicomponent reactions: utilization of 5-hydroxymethylfurfural (HMF) in the Biginelli reaction

International audienceThe use of the renewable platform molecule 5-hydroxymethylfurfural (HMF) in the multi-component Biginelli reaction has been investigated. Multicomponent reactions (MCR) using HMF offer straightforward access to novel fine chemicals. However, the peculiar reactivity and lower stability of HMF have limited its use in such strategies. In this paper, we report our results on the use of HMF in 3-component Biginelli reactions, leading in one single step to a series of functionalized dihydropyrimidinones obtained in moderate to good yields, with a broad substrate scope of 1,3-dicarbonyl compounds and urea building blocks. This is the first report on the use of HMF in this reaction. The CH 2 OH motif found in HMF provides useful functionalization for the target molecules, which cannot be offered by simpler aldehydes such as furfural

Efficient C-3 reductive alkylation of 4-hydroxycoumarin by dehydrogenative oxidation of benzylic alcohols through ruthenium

International audienceA practical route to prepare 4-hydroxycoumarin derivatives functionalized at the C-3 position is described through a catalytic coupling reaction between 4-hydroxycoumarin and a series of substituted benzylic alcohols. The reaction is conducted in the presence of tris(triphenylphosphine)ruthenium(II) dichloride (5 mol%), KOH (0.2 eq.) in tertamyl alcohol under microwave irradiation at 140 °C for 2 hours