2-substituted derivatives of adenosine and inosine cyclic 3',5'-phosphate. Synthesis, enzymic activity, and analysis of the structural requirements of the binding locale of the 2-substituent on bovine brain protein kinase.
A number of 2-substituted cyclic nucleotide derivatives were synthesized and investigated as activators of cAMP-dependent protein kinase and as substrates for and inhibitors of cAMP phosphodiesterase. Ring closure of 5-amino-1-beta-D-ribofuranosylimidazol-4-carboxamide cyclic 3',5'-phosphate (1) with various aldehydes according to a new procedure (Meyer, R. B., Jr., Shuman, D.A., and Robins, R. K. (1974), J. Am. Chem. Soc. 96, 4962) gave new derivatives of adenosine cyclic 3',5'-phosphate with the following 2-substituents: n-propyl, n-hexl, n-octyl, n-decyl, styryl, o-methoxyphenyl, and 2-thienyl. Alkylation of 2-mercaptoadenosine cyclic 3',5'-phosphate (20, Meyer et al., 1974) gave new cAMP derivatives with the following 2-substituent: ethylthio, n-propylthio, isopropylthio, allylthio, n-decylthio, and benzylthio. Deamination of 2-methyl-,2-n-butyl-, and 2-ethylthioadenosine cyclic 3',5'-phosphate. Using multiple regression analysis, a striking relationship was found between the relative potency of the compounds as activators of bovine brain cAMP-dependent protein kinase and parameters describing the hydrophobic, steric, and electronic character of the substituents on these compounds. All compounds were substrates for a cyclic nucleotide phosphodiesterase preparation from rabbit kidney. Additionally, the compounds were as a group, good inhibitors of the hydrolysis of cAMP by phosphodiesterase preparations from rabbit lung, beef heart, and dog heart.
D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000201:enzymology*; D002417:Cattle; D002855:Chromatography, Thin Layer; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000378:metabolism; D007289:Cyclic IMP / Q000031:analogs & derivatives / Q000378:metabolism; D007292:Inosine Nucleotides; D007700:Kinetics; D008168:Lung / Q000201:enzymology; D008433:Mathematics; D008968:Molecular Conformation; D009206:Myocardium / Q000201:enzymology; D009928:Organ Specificity; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism*; D011817:Rabbits; D011955:Receptors, Drug; D012044:Regression Analysis; D013045:Species Specificity; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship
D007292:Inosine Nucleotides; D011955:Receptors, Drug; D007289:Cyclic IMP; D000242:Cyclic AMP; D011494:Protein Kinases; D010727:Phosphoric Diester Hydrolases