Properties of base-substituted and carboxyl-esterified analogues of griseolic acid, a potent cAMP phosphodiesterase inhibitor.
Griseolic acid (GA) is a potent cyclic AMP (cAMP) phosphodiesterase (PDE) inhibitor that has an adenine base and two carboxyl groups in its molecule (Nakagawa F, Okazaki T, Naito A, Iijima Y and Yamazaki M, J Antibiot 38: 823-829, 1985). GA analogues were synthesized in which the adenine group was substituted with guanine (6-deamino-2-amino-6-hydroxygriseolic acid, G-GA) or hypoxanthine (6-deamino-6-hydroxygriseolic acid, H-GA). Their inhibitory activities to cyclic GMP (cGMP) PDE and cAMP PDE were compared with GA. For cGMP PDE from rod outer segments of bovine retina, the IC50 values of GA, G-GA and H-GA were 18, 0.040 and 0.12 microM, respectively, with 0.25 microM cGMP as substrate. For type IV PDE isozyme from mouse 3T3 fibroblast cells, the IC50 values of GA, G-GA and H-GA were 0.021, 15 and 11 microM, respectively, with 0.25 microM cAMP as substrate. Thus, GA and G-GA were found to be base-selective inhibitors of type IV PDE of 3T3 cells and type V PDE of bovine retinas, respectively. Esters of carboxylic acids of GA were synthesized in order to increase permeability into cells, and their efficacy was tested by measuring the accumulation of cAMP in 3T3 cells. The dipivaloyloxymethyl ester of GA was found to increase cAMP levels at 0.1 microM, while GA and 3-isobutyl-1-methylxanthine were active only above 100 microM, and the dimethyl ester of GA was inactive. The dipivaloyloxymethyl ester of GA seems to exert its activity after conversion to GA in the cell, since the pivaloyloxymethyl ester was easily hydrolysed by the enzyme action and the dipivaloyloxymethyl ester of GA itself was much less potent an inhibitor of PDE. The dipivaloyloxymethyl ester of GA inhibited thrombin-induced aggregation of platelets and stimulated lipolysis of adipocytes at low concentrations.
Yasumoto
T
T
New Lead Research Laboratories, Sankyo Co. Ltd, Tokyo, Japan.
Iijima
Y
Y
Kaneko
M
M
Yamazaki
M
M
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D016475:3T3 Cells / Q000187:drug effects / Q000201:enzymology; D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000273:Adipose Tissue / Q000187:drug effects / Q000201:enzymology; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D002417:Cattle; D002478:Cells, Cultured / Q000187:drug effects / Q000201:enzymology; D000242:Cyclic AMP / Q000032:analysis; D004952:Esters / Q000494:pharmacology; D051379:Mice; D011817:Rabbits; D012160:Retina / Q000187:drug effects / Q000201:enzymology; D012374:Rod Cell Outer Segment / Q000187:drug effects / Q000201:enzymology
D004952:Esters; C046499:griseolic acid; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D000241:Adenosine