Computer-Aided Molecular Design Laboratory, Mayo Clinic, Rochester, MN 55905, USA.
Sci Rep. 2012;2:631. doi: 10.1038/srep00631. Epub 2012 Sep 5.
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.
志贺样毒素和蓖麻毒素是核糖体失活蛋白 (RIPs)，对哺乳动物具有致命性，对全球健康构成威胁。目前尚无针对这些 RIP 的临床疫苗或疗法。两种小分子（Retro-1 和 Retro-2）通过高通量筛选被发现，并因其对细胞的 RIP 保护作用而被报道。Retro-2（报道为 (E)-2-(((5-甲基噻吩-2-基)亚甲基)氨基)-N-苯甲酰胺）具有重要意义，可完全保护小鼠免受致死性鼻内蓖麻毒素攻击。在此，我们报告的研究表明 Retro-2 的化学结构为 (±)-2-(5-甲基噻吩-2-基)-3-苯基-2,3-二氢喹唑啉-4(1H)-酮，而不是 (E)-2-(((5-甲基噻吩-2-基)亚甲基)氨基)-N-苯甲酰胺。后者是一种手性分子，会自发转化为前者，即外消旋体，并显示出对 RIP 的细胞保护作用。这引起了对手性分子 (±)-2-(5-甲基噻吩-2-基)-3-苯基-2,3-二氢喹唑啉-4(1H)-酮作为有前途的 RIP 抑制剂的关注，以及对高通量筛选获得的药物先导化合物进行化学表征的关注。
