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首页> 外文期刊>Journal of Medicinal Chemistry >Clavaric acid and steroidal analogues as Ras- and FPP-directed inhibitors of human farnesyl-protein transferase.
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Clavaric acid and steroidal analogues as Ras- and FPP-directed inhibitors of human farnesyl-protein transferase.

机译：克拉维酸和甾体类似物作为Ras和FPP指导的人类法呢基蛋白转移酶的抑制剂。

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We have identified a novel fungal metabolite that is an inhibitor of human farnesyl-protein transferase (FPTase) by randomly screening natural product extracts using a high-throughput biochemical assay. Clavaric acid [24, 25-dihydroxy-2-(3-hydroxy-3-methylglutaryl)lanostan-3-one] was isolated from Clavariadelphus truncatus; it specifically inhibits human FPTase (IC50 = 1.3 microM) and does not inhibit geranylgeranyl-protein transferase-I (GGPTase-I) or squalene synthase activity. It is competitive with respect to Ras and is a reversible inhibitor of FPTase. An alkaline hydrolysis product of clavaric acid, clavarinone [2,24,25-trihydroxylanostan-3-one], lacking the 3-hydroxy-3-methylglutaric acid side chain is less active as a FPTase inhibitor. Similarly, a methyl ester derivative of clavaric acid is also inactive. In Rat1 ras-transformed cells clavaric acid and lovastatin inhibited Ras processing without being overtly cytotoxic. Excess mevalonate reversed the effects of lovastatin but not of clavaric acid suggesting that the block on Ras processing by clavaric acid was due to inhibition of FPTase and not due to inhibition of HMG-CoA reductase. Despite these results, the possibility existed that clavaric acid inhibited Ras processing by directly inhibiting HMG-CoA reductase. To directly examine the effects of clavaric acid and clavarinone on HMG-CoA reductase, cholesterol synthesis was measured in HepG2 cells. No inhibition of HMG-CoA reductase was observed indicating that the inhibition of Ras processing by this class of compounds is due to inhibition of FPTase. To date, clavaric acid is the second reported nitrogen-free compound that competes with Ras to inhibit FPTase activity. A series of related compounds derived from computer-based similarity searches and subsequent rational chemical synthetic design provided compounds that exhibited a range of activity (0.04 --> 100 microM) against FPTase. Modest changes in the structures of these inhibitors dramatically change the inhibitory activity of these inhibitors.
机译：我们已经确定了一种新型的真菌代谢产物，它是通过高通量生化分析随机筛选天然产物提取物来抑制人法呢基蛋白转移酶（FPTase）的。从克拉瓦氏松果中分离出克拉瓦酸[24，25-二羟基-2-（3-羟基-3-甲基戊二烯基）羊毛脂-3-酮];它特异性抑制人FPTase（IC50 = 1.3 microM），不抑制香叶基香叶基蛋白转移酶-I（GGPTase-I）或角鲨烯合酶的活性。它与Ras竞争，并且是FPTase的可逆抑制剂。缺乏3-羟基-3-甲基戊二酸侧链的克拉维酸，克拉维酮[2,24,25-三羟基羊毛脂-3-酮]的碱性水解产物作为FPTase抑制剂的活性较低。类似地，克拉维酸的甲酯衍生物也没有活性。在Rat1 ras转化的细胞中，克拉维酸和洛伐他汀抑制了Ras的加工，而没有明显的细胞毒性。过量的甲羟戊酸逆转了洛伐他汀的作用，但并未逆转克拉维酸的作用，这表明克拉维酸对Ras加工的阻滞是由于FPTase的抑制而不是HMG-CoA还原酶的抑制。尽管有这些结果，但存在通过直接抑制HMG-CoA还原酶来抑制克拉斯酸的Ras加工的可能性。为了直接检查克拉维酸和克拉维酮对HMG-CoA还原酶的影响，在HepG2细胞中测量了胆固醇的合成。没有观察到HMG-CoA还原酶的抑制，表明该类化合物对Ras加工的抑制是由于FPTase的抑制。迄今为止，克拉维酸是第二种与Ras竞争抑制FPTase活性的无氮化合物。一系列基于计算机的相似性搜索和随后的合理化学合成设计衍生的相关化合物提供了针对FPTase表现出一定范围的活性（0.04-> 100 microM）的化合物。这些抑制剂结构的适度变化显着改变了这些抑制剂的抑制活性。

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