Design, synthesis, biological evaluation and molecular docking study of 2,4-diarylimidazoles and 2,4-bis(benzyloxy)-5-arylpyrimidines as novel HSP90 N-terminal inhibitors

Abstract

The molecular chaperone HSP90 plays an essential role in cancer occurrence and development. Therefore, it is an important target for the development of anticancer drugs. 1,3-Dibenzyl-2-aryl imidazolidine (8) is a previously reported inhibitor of HSP90; however, its anticancer activity is poor. In this work, chemical modification of 8 led to the discovery of 2,4-diarylimidazoles and 2,4-bis(benzyloxy)-5-arylpyrimidines as two types of novel HSP90 N-terminal inhibitors. 16l and 22k exhibited antiproliferative activity against multiple breast cancer cell lines with IC₅₀ values at the low micromolar level. 16l and 22k induced significant degradation of the client proteins AKT and ERK and a lower level of the heat shock response in comparison with tanespimycin (17-AAG). 22k exhibited a strong affinity for the HSP90α N-terminus with an IC₅₀ value of 0.21 μM. A molecular docking study revealed that 16l and 22k successfully bind to the geldanamycin binding site at the N-terminus of HSP90α.

Keywords:

• HSP90
• 2 4-diarylimidazoles
• 2 4-bis(benzyloxy)-5-arylpyrimidines
• molecular docking
• anticancer

Disclosure statement

The authors report no conflicts of interest.

Additional information

Funding

This work is funded by the Natural Science Foundation of Liaoning Province of China [Grant No. 2020-MS-105], and the Fundamental Research Funds for the Central Universities [Grant No. DUT20LK20; DUT22YG111].