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Saint-André-lez-Lille, France

Ghinet A.,University of Lille Nord de France | Ghinet A.,Laboratoire Of Pharmacochimie Hei | Rigo B.,University of Lille Nord de France | Rigo B.,Laboratoire Of Pharmacochimie Hei | And 6 more authors.

A new family of protein farnesyltransferase inhibitors, based on a ferrocene scaffold, was designed and synthesized. The biological evaluation of these compounds showed that ferrocenyl(2,3,4-trimethoxyphenyl)methanone (4c) and (ferrocen-1-yl)(2,3,4-trimethoxyphenyl)hydroxyimine (16) were two of the most active compounds, with protein farnesyltransferase inhibition potencies in the low micromolar range. The investigation of the influence of different bulky substituents (paracyclophane, noradamantane and adamantane) on the biological activity showed that these structural modifications abolished farnesyltransferase affinity. Molecular modeling studies revealed that the ferrocene unit of newly synthesized compounds was a well tolerated bulky group, for the A2 binding site of farnesyltransferase. Compounds were also evaluated for their antiproliferative activity on a NCI-60 cancer cell line panel. Paracyclophane derivative 13 exhibited the most potent in vitro cytostatic activity inhibiting the growth of MCF7, MDA-MB-468, T-47D and HT-29 cell lines. © 2012 The Royal Society of Chemistry. Source

Lucescu L.,Al. I. Cuza University | Gautret P.,University of Lille Nord de France | Gautret P.,Laboratoire Of Pharmacochimie Hei | Oudir S.,University of Lille Nord de France | And 8 more authors.
Synthesis (Germany)

The synthesis of dimethoxytriazine-containing N-aryl substituted pyrrolidinones is realized for the first time. Three new modes of reactivity for these substrates possessing a 4,6-dimethoxy-1,3,5-triazine unit are discussed. Their treatment with acid leads to complete O-demethylation of the methoxy groups, while similar reaction in a basic medium leads to partial O-demethylation. In contrast, heating in the presence of dimethyl sulfate as the catalyst induces migration of the methyl groups from the oxygen atoms to the triazine nitrogens (Hilbert-Johnson transposition). These new scaffolds may demonstrate biological potential. © Georg Thieme Verlag Stuttgart, New York. Source

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