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Identification of the first enantiopure Rac1–Tiam1 protein–protein interaction inhibitor and its optimized synthesis via phosphine free remote group directed hydroarylation

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Abstract

A phospine free hydroarylation reaction applied to norbornene derivatives is described for the first time and was exploited for the regioselective gram scale synthesis of AR-148, a known Rac1–Tiam1 PPI inhibitor. Umpolung conversion of the nitro group into free amine allowed the regiocontrol of the key arylation step via a long range effect. The effect of AR-148 in comparison with its enantiomers on Rac1 activation of has been evaluated and (−)AR-148 has been identified as the first enantiomerically pure inhibitor of Rac1–Tiam1 PPI.

Graphical abstract: Identification of the first enantiopure Rac1–Tiam1 protein–protein interaction inhibitor and its optimized synthesis via phosphine free remote group directed hydroarylation

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Publication details

The article was received on 24 Sep 2018, accepted on 21 Dec 2018 and first published on 26 Dec 2018


Article type: Research Article
DOI: 10.1039/C8MD00477C
Citation: Med. Chem. Commun., 2019, Advance Article
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    Identification of the first enantiopure Rac1–Tiam1 protein–protein interaction inhibitor and its optimized synthesis via phosphine free remote group directed hydroarylation

    A. Ruffoni, N. Ferri, A. Pinto, S. Pellegrino, A. Contini and F. Clerici, Med. Chem. Commun., 2019, Advance Article , DOI: 10.1039/C8MD00477C

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