Discovery of three-dimensional bicyclo[3.3.1]nonanols as novel heat shock protein 90 inhibitors.

We developed an efficient synthetic method for constructing bicyclo[3.3.1]nonane, an sp-carbon-rich three-dimensional scaffold consisting of two fused six-membered rings. Among the bicyclo[3.3.1]nonanols synthesized, several bicyclo[3.3.1]nonane derivatives were found to inhibit gene transcription by hypoxia-inducible factor-1 (HIF-1). The structure-activity relationship study revealed that the number of hydrophobic functional groups and a carboxylic acid moiety in the bicyclo[3.3.1]nonanols are important for inhibitory activities of both gene transcription by HIF-1 and cell growth. Bicyclo[3.3.1]nonanols fluctuated the amounts of client proteins of heat shock protein (HSP) 90 without inducing a heat shock response in cells and specifically inhibited the ATPase activity of HSP90. These results indicate that bicyclo[3.3.1]nonanols are novel HSP90 inhibitors with a different mechanism of action from conventional HSP90 inhibitors.