Stereoselective synthesis of (RP)-8-substituted-N6-acylated and N6-alkylated adenosine-3′,5′-cyclic phosphorothioic acids as cAMP antagonists

N6-Monoalkylated, N6-dialkylated and N6-acylated (RP)-adenosine 3′,5′-cyclic phosphorothioic acids have been prepared by stereoselective syntheses from cAMP for a study of protein kinase A antagonist activity. The antagonist activity of the parent primary 6-amino cAMP derivative was reduced after N-monoalkylation. No significant activity was detected in the N,N-dialkylated derivative. Mono N-acylation had little effect on the activity. Hydrogen bonding involving the 6-amino group in cAMPS seems necessary for activity.

Graphical abstractStereoselective P-amidation of cAMP substrates followed by stereocontrolled P-thiation. A general procedure for 6-aminations, and a process for chemoselective N6-acylation in cAMPS derivatives.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► 8-Substituted (RP)-cAMPS derivatives are antagonists of cAMP, corresponding (SP)-isomers agonists. ► Monoalkylation of the 6-amino group in (RP)-cAMPS gives less active antagonists. ► Excluding hydrogen bonding by dialkylation of the 6-amino group, leads to loss of antagonistic activity.