Synthesis and evaluation of Hsp90 inhibitors that contain the 1,4-naphthoquinone scaffold

Abstract

High-throughput screening of a library of diverse molecules has identified the 1,4-naphthoquinone scaffold as a new class of Hsp90 inhibitors. The synthesis and evaluation of a rationally-designed series of analogues containing the naphthoquinone core scaffold has provided key structure-activity relationships for these compounds. The most active inhibitors exhibited potent in vitro activity with low micromolar IC(50) values in anti-proliferation and Her2 degradation assays. In addition, 3g, 12, and 13a induced the degradation of oncogenic Hsp90 client proteins, a hallmark of Hsp90 inhibition. The identification of these naphthoquinones as Hsp90 inhibitors provides a new scaffold upon which improved Hsp90 inhibitors can be developed.

Figure 1

Natural Product inhibitors of Hsp90.

Figure 2

Structural similarity of novobiocin analogue (NA), derrubone, and naphthoquinone scaffolds.

Figure 3

Induced degradation of Hsp90 client proteins via 3g (top), 12 (middle), or 13a (bottom) inhibition of Hsp90. Compound, at varying concentrations, (μM) was evaluated for its ability to downregulate several client proteins as described in the Experimental Section. GA (500 nM) and DMSO were used as positive and negative controls, respectively.

Scheme 1

Suzuki coupling of naphthoquinone analogues.

Scheme 2

Preparation of acetamide and benzamide naphthoquinone analogues.

Scheme 3

Preparation of biaryl naphthoquinone analogues.

Scheme 4

Preparation of Benzamide Analogues.