Issue 9, 2012
From the journal:

MedChemComm

Discovery of ferrocene-containing farnesyltransferase inhibitors. Investigation of bulky lipophilic groups for the A2 binding site of farnesyltransferase

Alina Ghinet,ab   Benoît Rigo,*ab   Joëlle Dubois,c   Amaury Farce,ad   Jean-Pierre Hénicharta  and  Philippe Gautretab  

* Corresponding authors

a Univ Lille Nord de France, F-59000 Lille, France
E-mail: benoit.rigo@hei.fr

b UCLille, EA GRIIOT (4481), Laboratoire de Pharmacochimie, HEI, 13 rue de Toul, F-59046 Lille, France

c Institut de Chimie des Substances Naturelles, UPR2301 CNRS, Centre de Recherche de Gif, Avenue de la Terrasse, F-91198 Gif-sur-Yvette Cedex, France

d Institut de Chimie Pharmaceutique Albert Lespagnol, EA4481, IFR114, 3 Rue du Pr Laguesse, B.P. 83, F-59006 Lille, France

Abstract

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.

Graphical abstract: Discovery of ferrocene-containing farnesyltransferase inhibitors. Investigation of bulky lipophilic groups for the A2 binding site of farnesyltransferase

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Article information

DOI
https://doi.org/10.1039/C2MD20138K
Article type
Concise Article
Submitted
26 May 2012
Accepted
18 Jul 2012
First published
24 Jul 2012

Med. Chem. Commun., 2012,3, 1147-1154

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Discovery of ferrocene-containing farnesyltransferase inhibitors. Investigation of bulky lipophilic groups for the A2 binding site of farnesyltransferase

A. Ghinet, B. Rigo, J. Dubois, A. Farce, J. Hénichart and P. Gautret, Med. Chem. Commun., 2012, 3, 1147 DOI: 10.1039/C2MD20138K

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