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Synfacts 2018; 14(10): 0999
DOI: 10.1055/s-0037-1610902
DOI: 10.1055/s-0037-1610902
Synthesis of Natural Products and Potential Drugs
Synthesis of a Phosphoinositide 3-Kinase (PI3K) β Inhibitor
Further Information
Publication History
Publication Date:
17 September 2018 (online)
Key words
phosphoinositide 3-kinase β inhibitor - aldehyde oxidase - atropisomers - benzimidazole ring formation - 1,2,4-triazole ring formation - Suzuki–Miyaura coupling![](https://www.thieme-connect.de/media/synfacts/201810/i_k055_s1_10-1055_s-0037-1610902.gif)
Significance
The target molecule K is a phosphoinositide 3-kinase (PI3K) β Inhibitor that is of interest for the treatment of various cancers. The restricted axis of rotation around a carbon–nitrogen bond of rac-K generated atropisomeric compounds (P)-K and (M)-K with significantly different pharmacological and pharmacokinetic profiles.
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Comment
The metabolism of the inactive atropisomer (M)-K is the result of the action of the enzyme aldehyde oxidase (AO) whereas the active atropisomer (P)-K has lower affinity for AO resulting in better metabolic stability. The atropisomers (∆Erot = 35 kcal/mol) were separated by preparative chiral SFC chromatography.
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![](https://www.thieme-connect.de/media/synfacts/201810/i_k055_s1_10-1055_s-0037-1610902.gif)