The synthesis and evaluation of flavone and isoflavone chimeras of novobiocin and derrubone

Abstract

The natural products novobiocin and derrubone have both demonstrated Hsp90 inhibition and structure-activity relationships have been established for each scaffold. Given these compounds share several key structural features, we hypothesized that incorporation of elements from each could provide insight to structural features important for Hsp90 inhibition. Thus, chimeric analogues of novobiocin and derrubone were constructed and evaluated. These studies confirmed that the functionality present at the 3-position of the isoflavone plays a critical role in determining Hsp90 inhibition and suggests that the bicyclic ring system present in both novobiocin and derrubone do not share similar modes of binding.

Figure 1

Structures of novobiocin, A4, and A4-dimer.

Figure 2

Structure of derrubone.

Figure 3

Proposed overlay of novobiocin analogues (eg. 3) and 2 that were used to prepare flavone and isoflavone chimeras (4).

Figure 4

Novobiocin-derrubone chimeric analogues.

Figure 5

Western blot analysis of Hsp90 and Hsp90 client proteins against MCF-7 breast cancer cells. Concentrations (in μM) of 26b (top) and 37c (bottom) are indicated above each lane. GDA (geldanamycin, 500 nM) and DMSO were respectively employed as positive and negative controls.

Figure 6

Summary of structure–activity trends for chimeric analogues of novobiocin and derrubone.

Scheme 1

Representative retrosynthesis of isoflavone chimeric analogues.

Scheme 2

Preparation of 2-amido-flavone analogues.

Scheme 3

Preparation of 3-amido-isoflavone analogues.

Scheme 4

Preparation of (3,4-methylenedioxy)phenyl-isoflavone analogues.

Scheme 5

Preparation of 5-deoxy-derrubone analogues.