Discovery of novel indene-based hybrids as breast cancer inhibitors targeting Hsp90: Synthesis, bio-evaluation and molecular docking study
Amal M. Alosaimy, Amr S. Abouzied, Amani M.R. Alsaedi, Ahmed Alafnan, Abdulwahab Alamri, Mubarak A. Alamri, Mohammed Khaled Bin Break, Rehab Sabour, Thoraya A. Farghaly
Abstract
Inhibition of Heat-shock protein 90 (Hsp90) is considered an attractive route in fighting against cancer proliferation. Herein, new indene derivatives targeting Hsp90 were synthesized, and biologically evaluated. The new series of indeno-pyrimidine and indeno-pyridine were synthesized from the reaction of indene-enaminone with various heterocyclic amines and active methylene derivatives. Two breast cancer cell lines were used to examine the new compounds in vitro for their anticancer activity, namely, MCF-7 and MDA-MB231 cancer cells. The new indene derivatives 8a-c, 17a, and 25 displayed significant antitumor effect especially on MCF-7 cell line compared to doxorubicin. Derivative 8a was further subjected to Hsp90 enzyme assay aiming to ensure the inhibitory potential of such compound on Hsp90, it displayed IC50 = 18.79 ± 0.68 nM relative to Alvespimycin as a reference drug. Finally, molecular modeling of the most active compounds in the Hsp90 binding site was done presenting agreement with the in vitro anti-Hsp90 activity.