Synthesis and Biological Activity of 3-(Heteroaryl)quinolin-2(1 H)-ones Bis-Heterocycles as Potential Inhibitors of the Protein Folding Machinery Hsp90

Enrique L Larghi; Alexandre Bruneau; Félix Sauvage; Mouad Alami; Juliette Vergnaud-Gauduchon; Samir Messaoudi

doi:10.3390/molecules27020412

Synthesis and Biological Activity of 3-(Heteroaryl)quinolin-2(1 H)-ones Bis-Heterocycles as Potential Inhibitors of the Protein Folding Machinery Hsp90

Molecules. 2022 Jan 9;27(2):412. doi: 10.3390/molecules27020412.

Authors

Enrique L Larghi^{1

2}, Alexandre Bruneau², Félix Sauvage³, Mouad Alami¹, Juliette Vergnaud-Gauduchon³, Samir Messaoudi¹

Affiliations

¹ CNRS, BioCIS, Université Paris-Saclay, 92290 Châtenay-Malabry, France.
² Instituto de Química Rosario (IQUIR) CONICET/UNR, FBioyF, Rosario S2002LRK, Argentina.
³ CNRS, Institut Galien-Paris Saclay, Université Paris-Saclay, 92296 Châtenay-Malabry, France.

Abstract

In the context of our SAR study concerning 6BrCaQ analogues as C-terminal Hsp90 inhibitors, we designed and synthesized a novel series of 3-(heteroaryl)quinolin-2(1H), of types 3, 4, and 5, as a novel class of analogues. A Pd-catalyzed Liebeskind-Srogl cross-coupling was developed as a convenient approach for easy access to complex purine architectures. This series of analogues showed a promising biological effect against MDA-MB231 and PC-3 cancer cell lines. This study led to the identification of the best compounds, 3b (IC₅₀ = 28 µM) and 4e, which induce a significant decrease of CDK-1 client protein and stabilize the levels of Hsp90 and Hsp70 without triggering the HSR response.

Keywords: 3-(heteroaryl)quinolin-2(1H)-ones; 6BrCaQ; Hsp90; cytotoxicity; purines.

MeSH terms

HSP90 Heat-Shock Proteins*

Substances

HSP90 Heat-Shock Proteins