Author: Créquer-Grandhomme, Amandine ; Xie, Fang ; Cee, Victor J ; Jackson, Jeffrey J ; Sanders, Christiana ; Allen, John G ; Reed, Anthony B ; Manzanillo, Paolo ; Birkholz, Adam B ; Campuzano, Iain D G ; Hu, Ruozhen ; Bai, Wen-Ju ; Modak, Rucha V ; Lo, Mei-Chu ; Siegmund, Aaron C ; Javier, Noelle ; Sudom, Athena

B3GNT2 is responsible for elongation of cell surface long-chain polylactosamine, which influences the regulation of the immune response, making it an attractive target for immunomodulation. In the development of amide containing B3GNT2 inhibitors guided by structure-based drug design, imidazolones were found to successfully serve as amide bioisosteres. This novel imidazolone isosteric strategy alleviated torsional strain of the amide bond on binding to B3GNT2 and improved potency, isoform selectivity, as well as certain physicochemical and pharmacokinetic properties. Herein, we present the synthesis, SAR, X-ray cocrystal structures, and in vivo PK properties of imidazol-4-ones in the context of B3GNT2 inhibition.

Journal of Medicinal Chemistry

Imidazolone as an Amide Bioisostere in the Development of β-1,3-N-Acetylglucosaminyltransferase 2 (B3GNT2) Inhibitors

Author: Campuzano, Iain D. G. ; Jackson, Jeffrey J. ; Modak, Rucha V. ; Allen, John G. ; Birkholz, Adam B. ; Sanders, Christiana ; Lo, Mei-Chu ; Cee, Victor J. ; Xie, Fang ; Siegmund, Aaron C. ; Bai, Wen-Ju ; Javier, Noelle ; Reed, Anthony B. ; Crequer-Grandhomme, Amandine ; Manzanillo, Paolo ; Hu, Ruozhen ; Sudom, Athena

B3GNT2 is responsible for elongation of cell surface long-chain polylactosamine, which influences the regulation of the immune response, making it an attractive target for immunomodulation.In the development of amide containing B3GNT2 inhibitors guided by structure-based drug design, imidazolones were found to successfully serve as amide bioisosteres.This novel imidazolone isosteric strategy alleviated torsional strain of the amide bond on binding to B3GNT2 and improved potency, isoform selectivity, as well as certain physicochem. and pharmacokinetic properties.Herein, we present the synthesis, SAR, X-ray cocrystal structures, and in vivo PK properties of imidazol-4-ones in the context of B3GNT2 inhibition.

MoleculesQ3 · CHEMISTRY

Novel Coumarin-Containing Aminophosphonatesas Antitumor Agent: Synthesis, Cytotoxicity, DNA-Binding and Apoptosis Evaluation

Q3 · CHEMISTRY

ArticleOA

Author: Li, Ya-Jun ; Ye, Man-Yi ; Yao, Gui-Yang ; Wang, Cai-Yi ; Wang, Heng-Shan

A series of novel coumarin-containing α-aminophosphonates were synthesized and evaluated for their antitumor activities against Human colorectal (HCT-116), human nasopharyngeal carcinoma (human KB) and human lung adenocarcinoma (MGC-803) cell lines in vitro. Compared with 7-hydroxy-4-methylcoumarin (4-MU), most of the derivatives showed an improved antitumor activity. Compound 8j (diethyl 1-(3-(4-methyl-2-oxo-2H-chromen-7-yloxy) propanamido)-1-phenylethyl-Phosphonate), with IC50 value of 8.68 μM against HCT-116 cell lines, was about 12 fold than that of unsubstituted parent compound. The mechanism investigation proved that 8c, 8d, 8f and 8j were achieved through the induction of cell apoptosis by G1 cell-cycle arrest. In addition, the further mechanisms of compound 8j-induced apoptosis in HCT-116 cells demonstrated that compound 8j induced the activations of caspase-9 and caspase-3 for causing cell apoptosis, and altered anti- and pro-apoptotic proteins. DNA-binding experiments suggested that some derivatives bind to DNA through intercalation. The results seem to imply the presence of an important synergistic effect between coumarin and aminophosphonate, which could contribute to the strong chelating properties of aminophosphonate moiety.

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