Synthesis and evaluation of biotinylated sansalvamide A analogs and their modulation of Hsp90

Abstract

Described are the syntheses of three sansalvamide A derivatives that contain biotinylated tags at individual positions around the macrocycle. The tagged derivatives indicated in protein pull-down assays that they bind to Hsp90 at the same binding site (N-Middle domain) as the San A-amide peptide. Further, these compounds inhibit binding between Hsp90 and multiple C-terminal client proteins. This interaction is unique to the San A analogs indicating they can be tuned for selectivity against Hsp90 client/co-chaperone proteins.

Figure 1

Sansalvamide A molecules 1 and 2

Figure 2

Tagged Compound 2 with tags at positions I–IV

Figure 3

Pull-down data for compounds 2-T-I, 2-T-III, and 2-T-IV using mammalian Hsp90 domains: N, Middle, C, N-middle, and Middle-C domains respectively.

Figure 4

Compound 2 and client protein binding data

Figure 4

Compound 2 and client protein binding data

Figure 5

Model of how San A analogs interrupt binding between Hsp90 and key proteins

Scheme 1

General solid-phase synthesis of tagged derivatives