Synthesis of Acetaminophen Analogues Containing α-Amino Acids and Fatty Acids for Inhibiting Hepatotoxicity

Dedicated to Professor E. J. Corey on the occasion of his 90^th birthday.

Abstract

Acetaminophen is a popular antipyretic analgesic medicine that has weaker anti-inflammatory properties and lower incidence of side effects than nonsteroidal anti-inflammatory drugs (NSAIDs). However, acetaminophen causes hepatotoxicity due to the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI). We have obtained acetaminophen analogues in 57–99% yields by using aniline derivatives with protected α-amino acids and fatty acids via the corresponding mixed carbonic carboxylic anhydrides in aqueous MeCN. We have also succeeded in synthesizing AM404 analogues in 76–97% yields, which are expected to be promising candidates for reducing hepatotoxicity.

Key words

acetaminophen - hepatotoxicity - α-amino acid - fatty acid - AM404

• References

• 1 Baillie TA. Chem. Res. Toxicol. 2006; 19: 889
• 2a Chen C, Krausz KW, Idle JR, Gonzalez FJ. J. Biol. Chem. 2008; 283: 4543
• 2b Manyike PT, Kharasch ED, Kalhorn TF, Slattery JT. Clin. Pharmacol. Ther. 2000; 67: 275
• 2c Webster PA, Roberts DW, Benson RW, Kearns GL. J. Clin. Pharmacol. 1996; 36: 397
• 3 Högestätt ED, Jönsson BA. G, Ermund A, Andersson DA, Björk H, Alexander JP, Cravatt BF, Basbaum AI, Zygmunt PM. J. Biol. Chem. 2005; 280: 31405
• 4a Deshpande LS, DeLorenzo RJ. Neuroreport 2011; 22: 15
• 4b Ottani A, Leone S, Sandrini M, Ferrari A, Bertolini A. Eur. J. Pharmacol. 2006; 531: 280
• 5 Li G, Szostak M. Nat. Commun. 2018; 9: 4165
• 6a Ezawa T, Jung S, Kawashima Y, Noguchi T, Imai N. Bull. Chem. Soc. Jpn. 2017; 90: 689
• 6b Ezawa T, Kawashima Y, Noguchi T, Jung S, Imai N. Tetrahedron: Asymmetry 2017; 28: 266
• 6c Ezawa T, Jung S, Kawashima Y, Noguchi T, Imai N. Tetrahedron: Asymmetry 2017; 28: 75
• 6d Kawashima Y, Ezawa T, Yamamura M, Harada T, Noguchi T, Imai N. Tetrahedron Lett. 2016; 57: 668
• 6e Noguchi T, Jung S, Imai N. Tetrahedron Lett. 2014; 55: 394
• 6f Jung S, Tsukuda Y, Kawashima R, Ishiki T, Matsumoto A, Nakaniwa A, Takagi M, Noguchi T, Imai N. Tetrahedron Lett. 2013; 54: 5718
• 6g Noguchi T, Sekine M, Yokoo Y, Jung S, Imai N. Chem. Lett. 2013; 42: 580
• 6h Noguchi T, Jung S, Imai N. Chem. Lett. 2012; 41: 577
• 6i Noguchi T, Tehara N, Uesugi Y, Jung S, Imai N. Chem. Lett. 2012; 41: 42