Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10592533 | Bioorganic & Medicinal Chemistry Letters | 2012 | 4 Pages |
Abstract
Described is the synthesis of two biotinylated derivatives of a cytotoxic macrocycle. Pull-down assays indicate that this macrocycle targets the N-middle domain of Hsp90. Untagged compound can effectively compete away tagged compound-Hsp90 protein complexes, confirming the binding specificity of the macrocycle for Hsp90. The macrocycle is similar in potency to other structurally-related analogs of Sansalvamide A (San A) and induces apoptosis via a caspase 3 mechanism. Unlike other San A derivatives, we show that the macrocycle does not inhibit binding between C-terminal client proteins and co-chaperones and Hsp90, suggesting that it has a unique mechanism of action.
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Authors
Deborah M. Ramsey, Jeanette R. McConnell, Leslie D. Alexander, Kaishin W. Tanaka, Chester M. Vera, Shelli R. McAlpine,