Rapid construction of the cortistatin pentacyclic core
Rapid construction of the cortistatin pentacyclic core
复制标题
DOI：
10.1002/anie.200802203
复制
发表时间：
2008-01-01
影响因子：
16.6
通讯作者：
Sarpong, Richmond
中科院分区：
文献类型：
--
作者：
Simmons, Eric M.;Hardin, Alison R.;Sarpong, Richmond
血管生成，即形成新的毛细血管，是胚胎发育和伤口修复的重要过程。在正常情况下，这一过程受到严格的调控，并受到血管生成多肽的促进，如血管内皮生长因子(VEGF)、碱性成纤维细胞生长因子(BFGF)和血管生成素。[1]然而，血管生成也在肿瘤的生长和转移中发挥关键作用，血管生成抑制剂的发现使人们对其在癌症治疗中的潜在应用感到兴奋。当与传统化疗药物一起使用时，抗血管生成药物可以抑制肿瘤的复发，从而在一些动物模型中得到治愈。[2]与许多现有的化疗药物不同，抗血管生成药物通常毒性低，耐药性似乎不是一个大问题。[1B]这方面的研究还处于早期阶段，但最近Bevacizumab，一种抗血管内皮生长因子的单抗，被批准用于治疗结肠癌和乳腺癌。[3]由于这些有希望的初步结果，人们对发现和研究新的抗血管生成因子产生了浓厚的兴趣。在这里，我们报告了我们对抗血管生成化合物皮质抑素A(1，方案1)的初步合成研究。该化合物是Kobayashi及其同事于2006年从印度尼西亚海绵Cortisum Singex中分离得到的一个新的重排类固醇生物碱(1-4)家族的首批成员之一。[4]所有四个化合物都被发现具有显著的抗血管生成活性，其中最有效的是皮质抑素A(1)，对人脐静脉内皮细胞(HUVECs)的IC50值为1.8 nm，这是抗血管生成活性的标准模型。重要的是，这种高活性与相对于其他细胞类型的精致选择性(>；3000)相结合，因此反对将一般的细胞毒性作为一种作用模式。一年后，在首次分离报告之后，又发现了来自相同来源的另外七个家族成员，皮质酮E-L。[5]尽管它们与之前分离的同系物具有相同的五环核心，但皮质素E-H在其侧链中加入了N-甲基哌啶或3-甲基吡啶(见5-8，方案1)，而不是异喹啉片段。此外，ABC环北缘的不饱和和氧化的程度和位置与皮质素A-D不同。[5a]皮质酮J-L(9-11)在ABC环取代模式上表现出类似的变化，但在C17保留了异喹啉环。[5B]初步构效分析表明，异喹啉基团的存在对有效活性至关重要：而皮质素A-D和J-L被发现具有
Angiogenesis, the formation of new blood capillaries, is an essential process for embryonic development and wound repair. Under normal circumstances, this process is tightly regulated and is promoted by angiogenic polypeptides such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and angiogenin.[1] However, angiogenesis also plays a key role in tumor growth and metastasis, and the discovery of angiogenesis inhibitors has generated excitement about their potential use in the treatment of cancer. When administered alongside traditional chemotherapeutics, antiangiogenics suppress the recurrence of tumor growth, leading to curative treatment in some animal models.[2] In contrast to many existing chemotherapies, antiangiogenic therapy typically exhibits low toxicity and drug resistance does not appear to be a significant problem.[1b] Research in this area is in the early stages, but recently Bevacizumab, a monoclonal antibody against VEGF, was approved for the treatment of colon and breast cancers.[3] Because of these promising initial results, there is intense interest in the discovery and study of novel antiangiogenic factors. Herein, we report our initial synthetic studies on the antiangiogenic compound cortistatin A (1, Scheme 1). This compound is among the first members of a new family of rearranged steroidal alkaloids (1–4) that were isolated from the Indonesian marine sponge Corticium simplex in 2006 by Kobayashi and coworkers.[4] All four compounds were found to have significant antiangiogenic activity, with the most potent being cortistatin A (1), displaying an IC50 value of 1.8 nm against human umbilical vein endothelial cells (HUVECs), which is a standard model for antiangiogenic activity. Importantly, this high activity was coupled with an exquisite selectivity (> 3000) relative to other cell types, thus arguing against general cytotoxicity as a mode of action. This initial isolation report was followed a year later by the discovery of seven additional family members, cortistatins E–L, from the same source.[5] Although they share the same pentacyclic core as their previously isolated congeners, cortistatins E–H incorporate N-methylpiperidine or 3-methylpyridine in their side chains (see 5–8, Scheme 1) in place of the isoquinoline fragment. In addition, the degree and position of unsaturation and oxygenation along the northern edge of the ABC rings differs relative to cortistatins A–D.[5a] Cortistatins J–L (9–11) show similar variation in the ABC-ring substitution pattern, but retain the isoquinoline ring at C17.[5b] Preliminary structure–activity analysis suggests that the presence of the isoquinoline moiety is crucial for potent activity: while cortistatins A–D and J–L were found to have