Development of Dihydrodibenzooxepine Peroxisome Proliferator-Activated Receptor (PPAR) Gamma Ligands of a Novel Binding Mode as Anticancer Agents: Effective Mimicry of Chiral Structures by Olefinic E/Z-Isomers

Abstract

A novel class of PPARγ ligand 1 (EC 50 = 197 nM) with a dibenzoazepin scaffold was identified through highthroughput screening campaign. To avoid the synthetically troublesome chiral center of 1, its conformational analysis using the MacroModel was conducted, focusing on conformational flip of the tricyclic ring and the conformational restriction by the methyl group at the chiral center. On the basis of this analysis, scaffold hopping of dibenzoazepine into dibenzo[b,e]oxepine by replacing the chiral structures with the corresponding olefinic E/Z isomers was performed. Consequently, dibenzo[b,e]oxepine scaffold 9 was developed showing extremely potent PPARγ reporter activity (EC 50 = 2.4 nM, efficacy = 9.5%) as well as differentiation-inducing activity against a gastric cancer cell line MKN-45 that was more potent than any other well-known PPARγ agonists in vitro (94% at 30 nM). The X-ray crystal structure analysis of 9 complexed with PPARγ showed that it had a unique binding mode to PPARγ ligand-binding domain that differed from that of any other PPARγ agonists identified thus far.

First High-Resolution Crystal Structures of the Glucocorticoid Receptor Ligand-Binding Domain–Peroxisome Proliferator-Activated γ Coactivator 1-α Complex with Endogenous and Synthetic Glucocorticoids

“…There are only three structural investigations of PGC1a binding to LBDs from two NRs: liver receptor homolog 1 and PPARg (Li et al, 2008;Mays et al, 2017;Yamamoto et al, 2018). How PGC1a interacts with the GR LBD is still unknown.…”

Development of a novel class of peroxisome proliferator-activated receptor (PPAR) gamma ligands as an anticancer agent with a unique binding mode based on a non-thiazolidinedione scaffold

“…To eliminate the chiral center, its bioisosteric scaffolds were designed based on the conformational search of model substrates (R)-2' and (S)-2' (Figure 3). 23 As a result, we found that olefinic E/Z isomers 4 and 5 effectively mimic the chiral structures of (R)-2' and (S)-2', respectively, and discovered dihydrodibenzocycloheptene derivative 3, which has potent PPARγ reporter activity comparable to that of 2.…”

“…The synthetic compounds were evaluated in vitro via an HEK293 PPARγ reporter gene assay and cell aggregation assay to assess the differentiation-inducing activity against gastric cancer cell line MKN-45, as in our previous study. 23 In addition, compounds were treated with human liver microsome to investigate the metabolic stability.…”

“…We previously reported dibenzooxepine derivative 1, 23 which has a non-TZD structure. Compound 1, which was derived from high throughput screening hit compound dibenzoazepine derivative 2 (Figure 2), showed a unique binding mode and potent differentiation-inducing activity of cancer cells.…”

An Ugi Reaction/Intramolecular Cyclization/Oxidation Cascade towards Tetrazole-Linked Dibenzoxazepines

“…14 However, there are few studies on combining dibenzo[b,f] [1,4]oxazepine and 1,5disubstituted tetrazoles into a bis-heterocyclic system. [15][16][17][18][19] Moreover, dibenzo[b,f] [1,4]oxazepine is an attractive scaffold for de novo drug discovery due to its extended flat aromatic ring system, while having superior drug-like properties (such as cLogP and PSA) compared to its congeners (Figure 1). 20 Mycemycin (C) is an example of an anti-HIV natural product based on the tricyclic ring system.…”