2H55

Structural and quantum chemical studies of 8-aryl-sulfanyl adenine class Hsp90 inhibitors.

(2006) J Med Chem 49: 4953-4960

• PubMed: 16884307 Search on PubMed
• DOI: https://doi.org/10.1021/jm060297x
• Primary Citation of Related Structures:  
  2FWY, 2FWZ, 2H55


• PubMed Abstract: 
  

  Hsp90 chaperones play a critical role in modulating the activity of many cell signaling proteins and are an attractive target for anti-cancer therapeutics. We report here the structures of the water soluble 8-aryl-sulfanyl adenine class Hsp90 inhibitors, 1 (PU-H71) and 2 (PU-H64), in complex with the N-terminal domain of human Hsp90alpha. The conformation of 1 when bound to Hsp90 differs from previously reported 8-aryl adenine Hsp90 inhibitors including 3 (PU24FCl). While the binding mode for 3 places the 2'-halide of the 8-aryl group on top of the adenine ring, for 1 and 2, we show that the 2'-halide is rotated approximately 180 degrees away. This difference explains the opposing trends in Hsp90 inhibitory activity for the 2'-halo derivatives of the 3',4',5'-trimethoxy series where Cl > Br > I compared to the 4',5'-methylenedioxy series where I > Br > Cl. We also present quantum chemical calculations of 2 and its analogues that illuminate their basis for Hsp90 inhibition. The calculated conformation of 2 agreed well with the crystallographically observed conformations of 1 and 2. The predictive nature of the calculations has allowed the exploration of additional derivatives based on the 8-aryl adenine scaffold.

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Organizational Affiliation: 

Hauptman-Woodward Medical Research Institute, Buffalo, New York 14203, USA.