Synthesis of oleanolic acid dimers as inhibitors of glycogen phosphorylase.
Recently, oleanolic acid was found to be an inhibitor of glycogen phosphorylase. For further structural modification, we have synthesized several dimers of oleanolic acid by using amide, ester, or triazole linkage with click chemistry. The click chemistry was shown to be the most efficient method for the dimer synthesis. Nearly quantitative yield of triazole-linked dimers was obtained. Biological evaluation of the synthesized dimers as inhibitors of glycogen phosphorylase has been described. Four of six dimers exhibited inhibitory activity against rabbit muscle glycogen phosphorylase a (RMGPa), with compounds 2 and 7 as the most potent inhibitors, which displayed an IC(50) value (ca. 3 microM) lower than that of oleanolic acid (IC(50)=14 microM).
PPSM, ENS Cachan, CNRS, UniverSud, 61 av President Wilson, F-94230 Cachan.
Keguang
K
Cheng
Jun
J
Liu
Hongbin
H
Sun
Juan
J
Xie
D000818:Animals; D019281:Dimerization; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011817:Rabbits; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C550152:3,3'-(hexane-1,6-diylbis(1H-1,2,3-triazole-1,4-diylmethanediyloxy))bisolean-12-en-28-oic acid; D004791:Enzyme Inhibitors; D014230:Triazoles; C550151:iminobis(ethane-2,1-diylimino(3b)-28-oxoolean-12-ene-28,3-diyl) diacetate; D009828:Oleanolic Acid; D024981:Glycogen Phosphorylase