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

• Autores: Larghi, Enrique Leandro; Bruneau, Alexandre; Sauvage, Félix; Alami, Mouad; Vergnaud-Gauduchon, Juliette; Messaoudi, Samir
• Año de publicación: 2022
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: 3-(HETEROARYL)QUINOLIN-2(1H)-ONES; 6BRCAQ; CYTOTOXICITY; HSP90; PURINES
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

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.
Fil: Larghi, Enrique Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentina. Universite Paris-Saclay;
Fil: Bruneau, Alexandre. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentina
Fil: Sauvage, Félix. Universite Paris-Saclay;
Fil: Alami, Mouad. Universite Paris-Saclay;
Fil: Vergnaud-Gauduchon, Juliette. Universite Paris-Saclay;
Fil: Messaoudi, Samir. Universite Paris-Saclay;