CAMPS derivatives. A minireview over synthetic medicinal chemistry

Abstract

Cyclic nucleosides belonging to the cAMPS system can exert antagonistic or agonistic effects on the cAMP/PKA type 1 inhibitory pathway affecting T-lymphocyte replications. The stereochemistry at the phosphorus atom in the phosphate group is important for the expressed selectivity. The two stereoisomers at the phosphorus atom in the phosphate arise by selective replacements of one of the oxygens pendant from the phosphorus atom by a sulfur atom. Methods for the preparation of cAMPS derivatives as stereochemical mixtures at the phosphorus atom and separation of stereoisomers have been developed into highly stereoselective syntheses. Methods for halogenation in the purine 8-position afford corresponding halides. Heteronucleophilic substitution of the halides afford corresponding amines, ethers or sulfides. Transition metal catalysis for carbylation of the 8-halides affords simple and efficient routes for the preparation of 8-aryl, 8-hetaryl or 8-alkyl cAMPS derivatives. Preparations of prodrugs for improved cell membrane penetration are described. The prodrugs are S-alkylated derivatives which are constructed for selective cleavage of the SP bond by an esterase to regenerate the bioactive cAMPS species at the site of the desired action.