Chapter 30: The Chemical Modification of Cyclic AMP and Cyclic GMP.

Abstract

This chapter discusses the more recently reported procedures for substitution or modification of cyclic phosphates in various positions of the purine ring. With some exceptions modification of the ribose and cyclic phosphate moieties of cyclic nucleotides eliminates their biological activities. Two general routes for the synthesis of analogs have been pursued. The first involves the formation of the 3', 5' -cyclic phosphate ring from the corresponding nucleoside 5'-monophosphate. Earlier procedures to accomplish this were inefficient and have yielded only a few cyclic nucleotide derivatives. Cyclic AMP (cAMP) N-oxide was prepared by treatment of cAMP with m-chloroperbenzoic acid. Refluxing the specific organic compound in NaOAc-glacial HOAc gave 8-HO-cGMP and selenourea gave the 8-isoselenouronium (HBr)-cGMP that was treated with alkyl halides to yield 8-alkylseleno-cGMP derivatives. With the exception of the 8-NH2 derivatives the 8-substituted cyclic nucleosides are quite resistant to phosphodiesterase (PDE). Chloroacetaldehyde and cAMP gave 3-p-D-ribofuranosylimidazo[2,1-i] purine cyclic 3', 5'-phosphate. Similar reactions starting with 8-Br-, 8-CH3S-, and 8-PhCH2S-cAMP led to the corresponding 8-substituted-1, N-ethano-cAMP derivatives. The primary mechanism by which cyclic nucleotides exert their biological effects is probably via the cultivation of cyclic nucleotide-dependent protein kinases. One way to alter the intra-cellular levels of cyclic nucleotides is by supplying derivatives that are potent protein kinase activators, which possess tissue specificity and that are resistant to cyclic nucleotide PDE.