Access to 3-spiroindolizines containing an isoindole ring through intra-molecular arylation of spiro-N-acyliminium species: a new family of potent farnesyltransferase inhibitors

Anthony Pesquet; Hamid Marzag; Michael Knorr; Carsten Strohmann; Ata Martin Lawson; Alina Ghinet; Joëlle Dubois; Farce Amaury; Adam Daïch; Mohamed Othman

doi:10.1039/c8ob02612b

Journal articles

Access to 3-spiroindolizines containing an isoindole ring through intra-molecular arylation of spiro-N-acyliminium species: a new family of potent farnesyltransferase inhibitors

Anthony Pesquet ¹ Hamid Marzag ¹ Michael Knorr ² Carsten Strohmann ³ Ata Martin Lawson ¹ Alina Ghinet ⁴ Joëlle Dubois ⁵ Farce Amaury ⁶ Adam Daïch ^{1, *} Mohamed Othman ⁷

* Corresponding author

1 URCOM - Unité de Recherche en Chimie Organique et Macromoléculaire

2 UTINAM - Univers, Transport, Interfaces, Nanostructures, Atmosphère et environnement, Molécules (UMR 6213)

3 TU - Technische Universität Dortmund [Dortmund]

4 ICPAL - Institut de Chimie Pharmaceutique Albert Lespagnol

5 ICSN - Institut de Chimie des Substances Naturelles

6 LIRIC - Lille Inflammation Research International Center - U 995

7 ULH - Université Le Havre Normandie

Abstract : Based on N-acyliminium species, two efficient and rapid approaches to diversify spirocyclic systems connected by two different carbon centers to the isoindole ring have been developed. The imide reduction and the tandem oxidative cleavage of olefin/formyl-amide equilibration were at first selected as the key steps for these strategies. Ultimately the intramolecular α-amidoalkylation reaction was achieved through the arylation of α-acetoxy lactams or α-hydroxy lactams using, respectively, a Lewis acid or a Brønsted acid depending on the nature of N-acyliminium precursors. The latter led, in addition to the spiro-6-membered aza-heterocycles, to the formation of scarce spiro-5-membered analogues which show promising inhibitory activities on human farnesyltransferase in the nanomolar range demonstrating improved IC50 values of up to 1.5 nM.

Document type :

Journal articles

Domain :

Chemical Sciences

Chemical Sciences / Analytical chemistry

Chemical Sciences / Catalysis

Chemical Sciences / Organic chemistry

Chemical Sciences / Medicinal Chemistry

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https://hal-normandie-univ.archives-ouvertes.fr/hal-02332627
Contributor : Ata Martin Lawson <>
Submitted on : Thursday, October 24, 2019 - 9:26:02 PM
Last modification on : Wednesday, December 9, 2020 - 10:54:11 AM

Access to 3-spiroindolizines containing an isoindole ring through intra-molecular arylation of spiro-N-acyliminium species: a new family of potent farnesyltransferase inhibitors

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Access to 3-spiroindolizines containing an isoindole ring through intra-molecular arylation of spiro-N-acyliminium species: a new family of potent farnesyltransferase inhibitors

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