Synthetic oleanane and ursane triterpenoids with modified rings A and C: A series of highly active inhibitors of nitric oxide production in mouse macrophages
Synthetic oleanane and ursane triterpenoids with modified rings A and C: A series of highly active inhibitors of nitric oxide production in mouse macrophages
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DOI：
10.1021/jm0002230
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发表时间：
2000-11-02
影响因子：
7.3
通讯作者：
Gribble, GW
中科院分区：
文献类型：
--
作者：
Honda, T;Rounds, BV;Gribble, GW
我们设计并合成了16种具有不同修饰环C的新的烯-和-1-烯-3- 1三萜作为潜在的抗炎和癌症化学预防药物，并评估了它们对干扰素- γ诱导的小鼠巨噬细胞产生一氧化氮的抑制活性。研究发现，C环上的9(11)-烯-12- 1和12-烯-11- 1官能团与原12-烯相比，效价提高了约2-10倍。随后，我们设计并合成了新的含nit的olean-和our -1-烯-3- 1衍生物；上的腈和羧基。其中，我们发现甲基2-氰基3,12-二氧齐烷-1,9(11)-二氧齐烷-1,9(11)-二氧齐烷-1,9(11)-二氧齐烷-28-oic酸（CDDO）（28）和甲基2-羧基3,12-二氧齐烷-1,9(11)-二氧齐烷-1,9(11)-二氧齐烷-1,9(11)-二氧齐烷-1,9 -二氧齐烷-28-oic酸（29）具有极高的效价（IC50 = 0.1 nM）。它们的效力与地塞米松相似，尽管它们不通过糖皮质激素受体起作用。总的来说，修饰环A和C的组合比先导化合物3-氧齐烷-1,12-二烯-28-oic酸的效力提高了约10,000倍（IC50 = 1 muM水平）。所选择的齐墩烷三萜CDDO（26）在各种体外实验中被发现是一种有效的多功能药物，并显示出抗巯基乙酸酯-干扰素- γ诱导的小鼠腹膜炎的抗炎活性。
We have designed and synthesized 16 new olean- and urs-1-en-3-one triterpenoids with various modified rings C as potential antiinflammatory and cancer chemopreventive agents and evaluated their inhibitory activities against production of nitric oxide induced by interferon-gamma in mouse macrophages. This investigation revealed that 9(11)-en-12-one and 12-en-11-one functionalities in ring C increase the potency by about 2-10 times compared with the original 12-ene, Subsequently, we have designed and synthesized novel olean- and urs-1-en-3-one derivatives with nit;rile and carboxyl groups at. C-2 in ring A and with 9(11)-en-12-one and 12-en-11-one functionalities in ring C. Among them, we have found that methyl 2-cyano-3, 12-dioxoolcana-1,9(11)-dien-28-oate (26), 2-cyano-3, 12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) (28), and methyl 2-carboxy-3,12-dioxooleana-1,9(11)-dien-28-oate (29) have extremely high potency (IC50 = 0.1 nM level). Their potency is similar to that of dexamethasone although they do not act through the glucocorticoid receptor. Overall, the combination of modified rings A and C increases the potency by about 10 000 times compared with the lead compound, 3-oxooleana-1,12-dien-28-oic acid (8) (IC50 = 1 muM level). The selected oleanane triterpenoid, CDDO (26), was found to be a potent, multifunctional agent in various in vitro assays and to show antiinflammatory activity against thioglycollate-interferon-gamma -induced mouse peritonitis.