Novel synthetic oleanane and ursane triterpenoids with various enone functionalities in ring A as inhibitors of nitric oxide production in mouse macrophages
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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DOI：
10.1021/jm000008j
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发表时间：
2000-05-04
影响因子：
7.3
通讯作者：
Sporn, MB
中科院分区：
文献类型：
--
作者：
Honda, T;Gribble, GW;Sporn, MB
我们最初随机合成了约60个齐墩果烷和熊烷三萜类化合物作为潜在的抗炎和癌症化学预防剂。对这些衍生物在小鼠巨噬细胞中抑制干扰素-γ诱导的一氧化氮产生的初步筛选显示，3-氧代齐墩果-1，12-二烯-28-酸（B-15）显示出显著的活性（IC 50 = 5.6 μ M）基于B-15的结构，设计并合成了19个在A环C-2位有取代基的1-烯-3-酮结构单元的新的α-和乌苏-12-烯三萜类化合物。其中，在C-2处具有羧基、甲氧羰基和腈基的3-氧代齐墩果-1，12-二烯衍生物显示出比先导化合物B-15更高的活性。特别是2-羧基-3-氧代齐墩果-1，12-二烯-28-酸（3）在这组三萜类化合物中具有最高的活性（IC 50 = 0.07 μ M）。3的效力与氢化可的松相似（IC 50 = 0.01 μ M），尽管3不通过糖皮质激素受体起作用。有趣的构效关系，这些新的合成三萜类化合物进行了讨论。
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-gamma in mouse macrophages revealed that 3-oxooleana-1,12-dien-28-oic acid (B-15) showed significant activity (IC50 = 5.6 mu M) 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 mu M) ill this group of triterpenoids. The potency of 3 was similar to that of hydrocortisone (IC50 = 0.01 mu M), although 3 does not act through the glucocorticoid receptor. Interesting structure-activity relationships of these novel synthetic triterpenoids are also discussed.