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Pharmacophore Reassignment for Induction of the Immunosurveillance Cytokine TRAIL
Author(s) -
Jacob Nicholas T.,
Lockner Jonathan W.,
Kravchenko Vladimir V.,
Janda Kim D.
Publication year - 2014
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201402133
Subject(s) - pharmacophore , immunosurveillance , tumor necrosis factor alpha , chemistry , cytokine , stereochemistry , ligand (biochemistry) , cancer research , computational biology , receptor , biochemistry , immunology , medicine , biology , cell
Tumor necrosis factor (TNF)‐related apoptosis‐inducing ligand (TRAIL) is an immunosurveillance cytokine that kills cancer cells but demonstrates little toxicity against normal cells. While investigating the TRAIL‐inducing imidazolinopyrimidinone TIC10, a misassignment of its active structure was uncovered. Syntheses of the two isomers, corresponding to the published and reassigned structures, are reported. The ability of each to induce TRAIL expression in macrophages was investigated and it was found that only the compound corresponding to the reassigned structure shows the originally reported activity; the compound corresponding to the published structure is inactive. Importantly, this structural reassignment has furnished a previously unknown antitumor pharmacophore.