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

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

• Hsp90
• 6BrCaQ
• 3-(heteroaryl)quinolin-2(1<i>H</i>)-ones
• purines
• cytotoxicity