Development of Dihydrodibenzooxepine Peroxisome Proliferator-Activated Receptor (PPAR) gamma Ligands of a Novel Binding Mode as Anticancer Agents: …
Authors of this article are:
Yamamoto K, Tamura T, Henmi K, Kuboyama T, Yanagisawa A, Matsubara M, Takahashi Y, Suzuki M, Saito JI, Ueno K, Shuto S.
A summary of the article is shown below:
A novel class of PPARγligand 1 (EC50 = 197 nM) with a dibenzoazepin scaffold was identified through high-throughput 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. Based on 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 PPARγreporter activity (EC50 = 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 PPARγshowed that it had a unique binding mode to PPARγligand-binding domain that differed from that of any other PPARγagonists identified thus far.
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