Efficient synthesis and biological evaluation of epiceanothic acid and related compounds.
Epiceanothic acid (1) is a naturally occurring, but very rare pentacyclic triterpene with a unique pentacyclic triterpene (PT) structure. An efficient synthesis of 1 starting from betulin (3) has been accomplished in 12-steps with a total yield of 10% in our study. Compound 1 and selected synthetic intermediates were further evaluated as anti-HIV-1 agents, inhibitors of glycogen phosphorylase (GP), and cytotoxic agents. Compound 1 exhibited moderate HIV-1 inhibition. Most importantly, compound 5, with an opened A-ring, showed significant GP inhibitory activity with an IC(50) of 0.21 μM, suggesting a potential for development as an anti-diabetic agent. On the other hand, compound 12, with a closed A-ring, showed potent cytotoxicity against A549 and MCF-7 human tumor cell lines, with IC(50) values of 0.89 and 0.33 μM, respectively. These results suggest that the A-ring of PTs is an important pharmacophore that could be modified to involve different biological activities.
Center for Drug Discovery, College of Pharmacy, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China.
Pu
P
Zhang
Li
L
Xu
Keduo
K
Qian
Jun
J
Liu
Luyong
L
Zhang
Kuo-Hsiung
KH
Lee
Hongbin
H
Sun
D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D045744:Cell Line, Tumor; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D053978:Pentacyclic Triterpenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D014315:Triterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D000094062:Betulinic Acid
D019380:Anti-HIV Agents; D024981:Glycogen Phosphorylase; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; C557265:epiceanothic acid; C002503:betulin; D000094062:Betulinic Acid