title: Chemical structure of Retro-2, a compound that protects cells against ribosome-inactivating proteins.
abstract: Shiga-like toxins and ricin are ribosome-inactivating proteins (RIPs) that are lethal to mammals and pose a global health threat. No clinical vaccines or therapeutics currently exist to protect against these RIPs. Two small molecules (Retro-1 and Retro-2) were discovered with high-throughput screening and reported for their protection of cells against RIPs. Of great significance, Retro-2, reported as (E)-2-(((5-methylthiophen-2-yl)methylene)amino)-N-phenylbenzamide, fully protected mice from lethal nasal challenge with ricin. Herein, we report studies showing that the chemical structure of Retro-2 is (±)-2-(5-methylthiophen-2-yl)-3-phenyl-2,3-dihydroquinazolin-4(1H)-one rather than (E)-2-(((5-methylthiophen-2-yl)methylene)amino)-N-phenylbenzamide. The latter is an achiral molecule that converts spontaneously to the former, which is a racemate and showed cell protection against RIPs. This calls for attention to (±)-2-(5-methylthiophen-2-yl)-3-phenyl-2,3-dihydroquinazolin-4(1H)-one as a promising RIP inhibitor and for chemical characterization of drug leads obtained from high-throughput screens.
authors.affiliation: Computer-Aided Molecular Design Laboratory, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Jewn Giew
authors.initials: JG
authors.lastname: Park
authors.forename: Jennifer Nielsen
authors.initials: JN
authors.lastname: Kahn
authors.forename: Nilgun E
authors.initials: NE
authors.lastname: Tumer
authors.forename: Yuan-Ping
authors.initials: YP
authors.lastname: Pang
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002522:Chlorocebus aethiops; D019610:Cytoprotection; D004355:Drug Stability; D009682:Magnetic Resonance Spectroscopy; D000432:Methanol / Q000737:chemistry; D015394:Molecular Structure; D054788:Ribosome Inactivating Proteins; D012276:Ricin / Q000494:pharmacology*; D022641:Shiga Toxin 2 / Q000494:pharmacology*; D012997:Solvents / Q000737:chemistry; D013237:Stereoisomerism; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014709:Vero Cells
chemical_list: C549073:2-(((5-methyl-2-thienyl)methylene)amino)-N-phenylbenzamide; D001549:Benzamides; D022641:Shiga Toxin 2; D012997:Solvents; D013876:Thiophenes; D012276:Ricin; D054788:Ribosome Inactivating Proteins; D000432:Methanol