Discovery of Carboranes as Inducers of 20S Proteasome Activity
Discovery of Carboranes as Inducers of 20S Proteasome Activity
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发现碳硼烷作为 20S 蛋白酶体活性诱导剂
DOI：
10.1002/cmdc.201000112
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发表时间：
2010
期刊：
影响因子：
3.4
通讯作者：
Hiroyuki Nakamura
中科院分区：
文献类型：
--
作者：
H. Ban;Hidemitsu Minegishi;Kazuki Shimizu;Minako Maruyama;Yuka Yasui;Hiroyuki Nakamura
在真核生物中，蛋白酶体在大多数细胞内蛋白质的降解中起着至关重要的作用。泛素-蛋白酶体途径的降解控制着许多基本的细胞功能。这些包括细胞分化、细胞周期调节、信号转导途径、免疫反应中的抗原处理、应激信号、炎症反应和细胞凋亡。该途径的第一步是激活泛素激活酶(E1)，然后将泛素转移到泛素结合酶(E2)。第二步是通过泛素连接酶(E3)将泛素从E2转移到底物。然后，这种多泛素化的蛋白质被26S蛋白酶体降解。26S蛋白酶体由一个20S蛋白酶体圆柱体组成，两端各有一个调控的19S复合体。20S蛋白酶体具有三种主要的蛋白分解活性：caspase样蛋白(B1)、胰蛋白酶样蛋白(B2)和胰凝乳酶样蛋白(B5)。19S复合体(PA700)激活泛素结合蛋白的蛋白酶体降解。除了PA700，20S蛋白酶体还可以单独与其他调控复合体相互作用，如PA28或PA200。这两种复合体都可以利用多肽底物激活20S蛋白酶体。许多天然和合成的蛋白酶体抑制剂已经被开发出来，如多肽醛、多肽环氧酮、多肽乙烯基砜、乳糖体和多肽硼酸盐。多肽硼酸盐PS-341(Bortezomib)是一种20S蛋白酶体胰凝乳酶样活性的抑制剂，已被批准用于多发性骨髓瘤的治疗。小分子蛋白酶体激活剂的开发程度较低。包括十二烷基硫酸钠(十二烷基硫酸钠)、脂肪酸、神经酰胺硫酸盐、溶血磷脂酰肌醇和心磷脂在内的几种生物脂类被观察到可以激活20S蛋白酶体。总体而言，这些分子对合成底物的蛋白酶体降解更具变异性，但并不显著。研究了多肽激活剂对蛋白酶体的戏剧性激活作用。近年来，桦木酸(BA)因其抗HIV-1和抗肿瘤活性而备受关注。BA及其二甲基琥珀酸衍生物(DSB)分别是20S蛋白酶体b5和b1活性的优先激活剂。碳硼烷(二碳杂环十二烷；C2B10H12)具有显著的热稳定性，其二十面体几何构型和特殊的疏水性质可能使其在与目标蛋白质疏水相互作用的生物活性分子中用作疏水药效团。在这项研究中，我们发现在没有PA28的情况下，邻碳硼衍生物有可能诱导20S蛋白酶体的b1、b2和b5活性。邻甲基苯酚及其酯类化合物的合成如方案一所示。在K2CO3存在下，4-碘苯酚(1)与溴化苯反应进行了苯甲化反应。在催化剂PdCl2(PPh_3)_2和CuI存在下，生成的苄基醚2与乙炔基三甲基硅烷发生Sonogashira偶联反应。反应在密封的小瓶中进行，微波辐射(120 8℃)。反应在25min内完成，以98%的产率得到了相应的偶联产物。在四氢呋喃水溶液中用LiOH处理除去TMS基团，得到定量产率的炔基3。在乙腈(5当量)存在下，以甲苯为溶剂回流反应，以25%的产率得到相应的碳硼烷4。用加氢还原脱除了苯基。
In eukaryotes, proteasomes play a critical role in the degradation of most intracellular proteins. Degradation by ubiquitin-proteasome pathway controls many fundamental cellular functions. These include cell differentiation, cell-cycle regulation, signal transduction pathways, antigen processing in immune responses, stress signaling, inflammatory responses, and apoptosis. The first step in the pathway is activation of ubiquitin-activating enzyme (E1), followed by ubiquitin transfer to an ubiquitin-conjugating enzyme (E2). The second step is transfer of ubiquitin from E2 to the substrate by ubiquitin ligase (E3). The polyubiquitinated protein is then degraded by a 26S proteasome. The 26S proteasome comprises of a 20S proteasome cylinder capped by a regulatory 19S complex at each extremity. The 20S proteasome has three major proteolytic activities : caspase-like (b1), trypsin-like (b2), and chymotrypsin-like (b5). The 19S complex (PA700) activates proteasome degradation of ubiquitin-conjugated proteins. In addition to PA700, 20S proteasome can separately interact with other regulatory complexes such as PA28 or PA200. Both complexes can activate the 20S proteasome using peptide substrates. Many natural and synthetic inhibitors of the proteasome have been developed, such as peptide aldehydes, peptide epoxyketones, peptide vinyl sulfones, lactacystins, and peptide boronates. The peptide boronate PS-341 (bortezomib), an inhibitor of the chymotrypsin-like activity of 20S proteasome, has been approved for the treatment of multiple myeloma. Small-molecule proteasome activators have been developed to a lesser extent. Several biological lipids, including sodium dodecyl sulfate (SDS), fatty acids, ceramide sulfates, lysophosphatidylinositol, and cardiolipin have been observed to activate the 20S proteasome. In general, proteasomal degradation of synthetic substrates by these molecules is more variable but not remarkable. Dramatic activation of proteasome by peptide-based activators has been investigated. Recently, betulinic acid (BA) has attracted attention for its anti-HIV-1 and antitumor activities. BA and its dimethylsuccinyl derivative (DSB) were found to be preferential activators of the b5 and b1 activities of the 20S proteasome, respectively. Carboranes (dicarba-closo-dodecaboranes; C2B10H12) exhibit remarkable thermal stability, and their icosahedral geometry and exceptional hydrophobic property may allow their use as a hydrophobic pharmacophore in biologically active molecules that interact hydrophobically with target proteins. In this study, we discovered that ortho-carborane derivatives have the potential to induce the b1, b2, and b5 activities of the 20S proteasome in the absence of PA28. The synthesis of ortho-carboranyl phenol and its ester derivatives is shown in Scheme 1. Benzylation was performed by treating 4-iodophenol (1) with benzyl bromide in the presence of K2CO3. The resulting benzyl ether 2 underwent the Sonogashira coupling reaction with ethynyltrimethylsilane in the presence of catalysts, PdCl2(PPh3)2 and CuI. The reaction was performed in a sealed vial under microwave-irradiated (120 8C). The reaction reached completion within 25 min to give the corresponding coupling product in 98 % yield. The TMS group was removed by treatment with LiOH in aqueous THF solution to afford alkyne 3 in quantitative yield. The reaction of alkyne 3 with decaborane proceeded in the presence of acetonitrile (5 equiv) in toluene at reflux to give the corresponding carborane 4 in 25 % yield. The benzyl group was removed by hydro-
DOI：
10.1016/0006-291x(81)91823-4
发表时间：
1981-08
影响因子：
3.1
作者：
Narian Orlowski;Sherwin Wilk
通讯作者：
Narian Orlowski;Sherwin Wilk