title: Synthesis and enzymatic activity of some new purine ring system analogues of adenosine 3',5'-cyclic monophosphate.
abstract: A series of novel adenosine 3',5'-cyclic monophosphate (cAMP) analogues, as well as their 6-deamino and 6-nitro derivatives, were synthesized where the purine ring was replaced by indazole, benzotriazole, and benzimidazole. The 3',5'-cyclic monophosphates of indazole and benzotriazole ribofuranosides, where the sugar-phosphate moiety is attached to the N-2 nitrogen atoms of the heterocycles, were also prepared. The biological efficiency of the analogues was tested by their ability to activate purified cAMP-dependent protein kinase I (PK-I) from rabbit skeletal muscle and cAMP-dependent protein kinase II (PK-II) from bovine heart. Each cyclic nucleotide is capable of activating both PK isozymes in half-maximum concentrations (Ka) ranging from 2.0 x 10(-8) to 4.8 x 10(-6) M. The cyclic phosphate of N-1-beta-D-ribofuranosylindazole (13) proved to be a very poor activator for both PK-I and PK-II, but when indazole binds by N-2 to ribose or when the hydrogen atom at C-4 is substituted by a nitro or amino group, activities of the analogues increase considerably. The activating potencies of benzotriazole derivatives are similar to that of cAMP, irrespective of the C-4 substituents. The Ka' values of cyclic nucleotides containing benzimidazole were found to be higher for PK-II than for PK-I; e.g. the activity of 4-nitro-1-beta-D-ribofuranosylbenzimidazole 3',5'-cyclic monophosphate (32) is nearly 20 times as high for PK-II than for PK-I.
authors.affiliation: Central Research Institute for Chemistry, Hungarian Academy of Sciences, Budapest.
authors.forename: G
authors.initials: G
authors.lastname: Sági
authors.forename: K
authors.initials: K
authors.lastname: Szũcs
authors.forename: G
authors.initials: G
authors.lastname: Vereb
authors.forename: L
authors.initials: L
authors.lastname: Otvös
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D002417:Cattle; D000242:Cyclic AMP / Q000031:analogs & derivatives*; D004789:Enzyme Activation / Q000187:drug effects; D007191:Indazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D015394:Molecular Structure; D009132:Muscles / Q000201:enzymology; D009206:Myocardium / Q000201:enzymology; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D011817:Rabbits; D012266:Ribose / Q000378:metabolism; D013057:Spectrum Analysis; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D001562:Benzimidazoles; D007191:Indazoles; D014230:Triazoles; D012266:Ribose; C012771:benzotriazole; D000242:Cyclic AMP; D011494:Protein Kinases