Novel Synthetic Oleanane and Ursane Triterpenoids with Various Enone Functionalities in Ring A as Inhibitors of Nitric Oxide Production in Mouse Macrophages

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Abstract
We initially randomly synthesized about 60 oleanane and ursane triterpenoids as potential anti-inflammatory and cancer chemopreventive agents. Preliminary screening of these derivatives for inhibition of production of nitric oxide induced by interferon-γ in mouse macrophages revealed that 3-oxooleana-1,12-dien-28-oic acid (B-15) showed significant activity (IC50 = 5.6 μM). On the basis of the structure of B-15, 19 novel olean- and urs-12-ene triterpenoids with a 1-en-3-one functionality having a substituent at C-2 in ring A have been designed and synthesized. Among them, 3-oxooleana-1,12-diene derivatives with carboxyl, methoxycarbonyl, and nitrile groups at C-2 showed higher activity than the lead compound B-15. In particular, 2-carboxy-3-oxooleana-1,12-dien-28-oic acid (3) had the highest activity (IC50 = 0.07 μM) in this group of triterpenoids. The potency of 3 was similar to that of hydrocortisone (IC50 = 0.01 μM), although 3 does not act through the glucocorticoid receptor. Interesting structure−activity relationships of these novel synthetic triterpenoids are also discussed.