ABSTRACT
Mnk1 and Mnk2 are protein kinases responsible for phosphorylating eIF4E, a eukaryotic initiation factor responsible for initiating translation. Inhibiting Mnk1 and Mnk2 could therefore play a role in treating metabolic diseases such as cancer, diabetes, and hyperlipidemia. A wide range of sulfoximine substituted quinazolines were synthesised and evaluated for their Mnk1 and Mnk2 inhibitory activity. Amongst these compounds, 26 quinazolines showed activity against Mnk1 at <100 nM and 54 showed activity against Mnk2 at 1 nM. The results indicate that this scaffold is much more active against Mnk2 than Mnk1. The synthesised compounds may be future drugs in the treatment of metabolic diseases.
Article highlights
Sulfoximine substituted quinazolines are potent Mnk1 and Mnk2 inhibitors.
The sulfoximine substituted quinazoline derivatives were more active against Mnk2 than Mnk1.
Sulfoximine substituted quinazolines are lead compounds for the treatment of metabolic diseases such as cancer and diabetes.
The sulfoximine moiety is most easily synthesised with sodium azide and sulphuric acid or o-mesitylenesulfonylhydroxylamine.
Variation at the 4, 5 and 7 positions lead to a variety of sulfoximine substituted quinazoline derivatives.This box summarizes key points contained in the article.