Dataset Information

Identification and Structure-Activity Studies of 1,3-Dibenzyl-2-aryl imidazolidines as Novel Hsp90 Inhibitors.

ABSTRACT: Hsp90 (Heat shock protein 90) is involved in various processes in cancer occurrence and development, and therefore represents a promising drug target for cancer therapy. In this work, a virtual screening strategy was employed, leading to the identification of a series of compounds bearing a scaffold of 1,3-dibenzyl-2-aryl imidazolidine as novel Hsp90 inhibitors. Compound 4a showed the highest binding affinity to Hsp90? (IC50 = 12 nM) in fluorescence polarization (FP) competition assay and the strongest anti-proliferative activity against human breast adenocarcinoma cell line (MCF-7) and human lung epithelial cell line (A549) with IC50 values of 21.58 ?M and 31.22 ?M, respectively. Western blotting assays revealed that these novel Hsp90 inhibitors significantly down-regulated the expression level of Her2, a client protein of Hsp90, resulting in the cytotoxicity of these novel Hsp90 inhibitors. The molecular docking study showed that these novel Hsp90 inhibitors bound to the adenosine triphosphate (ATP) binding site at the N-terminus of Hsp90. Furthermore, structure-activity relationship studies indicated that the N-benzyl group is important for the anti-cancer activity of 1,3-dibenzyl-2-aryl imidazolidines.

SUBMITTER: Liu Y

PROVIDER: S-EPMC6600241 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Identification and Structure-Activity Studies of 1,3-Dibenzyl-2-aryl imidazolidines as Novel Hsp90 Inhibitors.

Liu Yajun Y Liu Xiaoxia X Li Lihong L Dai Rui R Shi Meiyun M Xue Hongyu H Liu Yong Y Wang Hecheng H

Molecules (Basel, Switzerland) 20190603 11

Hsp90 (Heat shock protein 90) is involved in various processes in cancer occurrence and development, and therefore represents a promising drug target for cancer therapy. In this work, a virtual screening strategy was employed, leading to the identification of a series of compounds bearing a scaffold of 1,3-dibenzyl-2-aryl imidazolidine as novel Hsp90 inhibitors. Compound <b>4a</b> showed the highest binding affinity to Hsp90α (IC<sub>50</sub> = 12 nM) in fluorescence polarization (FP) competitio ...[more]

PMID: 31163701

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Project description:The recent reduction in mortality due to malaria is being threatened by the appearance of Plasmodium falciparum parasites that are resistant to artemisinin in Southeast Asia. To limit the impact of resistant parasites and their spread across the world, there is a need to validate anti-malarial drug targets and identify new leads that will serve as foundations for future drug development programmes targeting malaria. Towards that end, the antiplasmodial potential of several Hsp90 inhibitors was characterized. Because, the Hsp90 chaperone has been suggested as a good drug target against multiple parasitic infections including malaria.Chemically diverse sets of Hsp90 inhibitors, evaluated in clinical trials as anti-cancer agents, were tested against the malaria parasite. Most of the compounds showed strong antiplasmodial activity in growth inhibition assays against chloroquine sensitive and resistant strains. There was a good agreement between the compound in vitro anti-parasitic activity and their affinity against the Plasmodium chaperone. The two most potent Hsp90 inhibitors also showed cytocidal activity against two P. falciparum strains. Their antiplasmodial activity affected all parasite forms during the malaria blood cycle. However, the compounds activity against the parasite showed no synergy when combined with anti-malarial drugs, like chloroquine or DHA.The Hsp90 inhibitors anti-parasitic activity correlates with their affinity to their predicted target the P. falciparum chaperone Hsp90. However, the most effective compounds also showed high affinity for a close homologue, Grp94. This association points to a mode of action for Hsp90 inhibitors that correlate compound efficacy with multi-target engagement. Besides their ability to limit parasite replication, two compounds also significantly impacted P. falciparum viability in vitro. Finally, a structural analysis suggests that the best hit represents a promising scaffold to develop parasite specific leads according.The results shown that Hsp90 inhibitors are lethal against the malaria parasite. The correlation between biochemical and in vitro data strongly supports Hsp90 as a drug target against the malaria parasite. Furthermore, at least one Hsp90 inhibitor developed as anticancer therapeutics could serve as starting point to generate P. falciparum-specific lead compounds.

Dataset Information

Identification and Structure-Activity Studies of 1,3-Dibenzyl-2-aryl imidazolidines as Novel Hsp90 Inhibitors.

Publications

Identification and Structure-Activity Studies of 1,3-Dibenzyl-2-aryl imidazolidines as Novel Hsp90 Inhibitors.

Similar Datasets

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