Amide-tethered quinoline-resorcinol conjugates as a new class of HSP90 inhibitors suppressing the growth of prostate cancer cells.

• Quinoline – resorcinol hybrid constructs were designed and synthesized. • Compound 11 displayed potent cell growth inhibitory effects against PC-3 cell lines with GI 50 value of 0.14 µM. • The antiproliferative effects of 11 were mediated through Hsp90 chaperone inhibition. • Compound 11 demonstrated apoptosis inducing ability and caused G2M phase cell cycle arrest. • Docking studies revealed key interactions of 11 with amino acid residues of the HSP90 chaperone protein. The study is focused on the design and synthesis of amide tethered quinoline-resorcinol hybrid constructs as a new class of HSP90 inhibitor. In-vitro studies of the synthetic compounds led to the identification of compound 11 , which possesses potent cell growth inhibitory effects against HCT116, Hep3B and PC-3 cell lines, exerted through HSP90 inhibition. Compound 11 triggers degradation of HSP90 client proteins along with concomitant induction of HSP70, demonstrates apoptosis inducing ability and causes G2M phase cell cycle arrest in PC-3 cells. Molecular modeling was used to dock compound 11 into the HSP90 active site and key interactions with the amino acid residues of the HSP90 chaperone protein were determined. [ABSTRACT FROM AUTHOR]