Synthesis and Biological Activity of 3-(Heteroaryl)quinolin-2(1 H)-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: 3-(heteroaryl)quinolin-2(1H)-ones; 6BrCaQ; Hsp90; cytotoxicity; purines.

Figure 1

Structure of novobiocin and 6BrCaQ compounds and the approach for the design of targeted compounds 3, 4 and 5.

Scheme 1

Synthetic strategy to target 3-(heteroaryl)quinolin-2(1H)-ones 3.

Scheme 2

Synthetic strategy to target 3-(purino)-quinolin-2(1H)-ones 4a–h.

Scheme 3

Synthetic strategy to target 3-adenines-quinolin-2(1H)-ones 5a,b.

Figure 2

Effects of quinolone analogues 3a–e, 4e and 5b on HSP90 machinery protein levels and on CDK-4 stability. PC-3 cells were grown and exposed to Hsp90 inhibitors (3a–e, 4e and 5b, 15 µM) as described in Experimental section for 72 h and cell lysates were analyzed by Western blotting with regard to the levels of CDK-4, Hsp90α/β and Hsp70. NT corresponds to untreated cells; D, DMSO-treated cells were used as controls, GADPH level is used for control in protein loading on gels.