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From simple quinoxalines to potent oxazolo[5,4-f]quinoxaline inhibitors of glycogen-synthase kinase 3 (GSK3)

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Abstract

2,7-Disubstituted oxazolo[5,4-f]quinoxalines were synthesized from 6-amino-2-chloroquinoxaline in four steps (iodination at C5, substitution of the chloro group, amidation and copper-catalysed cyclization) affording 28 to 44% overall yields. 2,8-Disubstituted oxazolo[5,4-f]quinoxaline was similarly obtained from 6-amino-3-chloroquinoxaline (39% overall yield). For the synthesis of other oxazolo[5,4-f]quinoxalines, amidation was rather performed before substitution; moreover, time-consuming purification steps were avoided between the amines and the final products (38 to 54% overall yields). Finally, a more efficient method involving merging of the last two steps in a sequential process was developed to access more derivatives (37 to 65% overall yields). Most of the oxazolo[5,4-f]quinoxalines were evaluated for their activity on a panel of protein kinases, and a few 2,8-disubstituted derivatives proved to inhibit GSK3 kinase. While experiments showed an ATP-competitive inhibition on GSK3β, structure–activity relationships allowed us to identify 2-(3-pyridyl)-8-(thiomorpholino)oxazolo[5,4-f]quinoxaline as the most potent inhibitor with an IC50 value of about 5 nM on GSK3α.

Graphical abstract: From simple quinoxalines to potent oxazolo[5,4-f]quinoxaline inhibitors of glycogen-synthase kinase 3 (GSK3)

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Publication details

The article was received on 12 Sep 2019, accepted on 27 Nov 2019 and first published on 27 Nov 2019


Article type: Paper
DOI: 10.1039/C9OB02002K
Org. Biomol. Chem., 2020, Advance Article

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    From simple quinoxalines to potent oxazolo[5,4-f]quinoxaline inhibitors of glycogen-synthase kinase 3 (GSK3)

    F. Lassagne, C. Duguépéroux, C. Roca, C. Perez, A. Martinez, B. Baratte, T. Robert, S. Ruchaud, S. Bach, W. Erb, T. Roisnel and F. Mongin, Org. Biomol. Chem., 2020, Advance Article , DOI: 10.1039/C9OB02002K

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