Design, synthesis and pharmacological evaluation of 4,5-diarylisoxazols bearing amino acid residues within the 3-amido motif as potent heat shock protein 90 (Hsp90) inhibitors.
Zhang C, Wang X, Liu H, Zhang M, Geng M, Sun L, Shen A, Zhang A.
A structure-based medicinal chemistry optimization was conducted on the clinical Hsp90 inhibitor diarylisoxazole 3. Several series of new compounds were designed and synthesized by incorporating diversified amino acid derivatives with various lengths to the 3-amido motif of the isoxazole scaffold. Compound 14j was identified to have high Hsp90 binding potency (14 nM) and antiproliferative activity against H3122 human lung cancer and BT-474 breast cancer cells. Treatment of 14j with H3122 cell led to degradation of client protein ALK, reduction of downstream phosphorylation of AKT and ERK, and up-regulation of Hsp70. Molecular docking suggested that the terminal valine moiety and the ethyleneglycol linker in compound 14j formed additional apolar and polar interaction network with a number of amino acid residues.