Synthesis of Anticancer Agents Using Prins Cyclizations

使用 Prins 环化合成抗癌剂

• 批准号: 6400176
• 负责人: SCOTT D. RYCHNOVSKY
• 金额: $ 23.69万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6400176
• 关键词: antineoplastics; biological products; chemical synthesis; cyclization; drug design /synthesis /production; heterocyclic compounds; oxazoles; stereochemistry

The principle synthetic target in this proposal is phorboxazole B, a remarkably potent anticancer agent. Phorboxazole B was tested against the NCI's panel tumor cell lines and was found, for example, to inhibit the growth of colon tumor cells HCT-116 (GI50 4.36 X 10(-10) M). Two of the key segments of phorboxazole were prepared in the previous grant period using our segment-coupling Prins cyclization. Completion of the synthesis will be accomplished by assembly of the macrolide A and attaching the side chain B . Synthetic phorboxazole will be made available to collaborators to evaluate its mode of action, and to evaluate its potential as an anticancer agent. We are developing Prins cyclizations for the synthesis of complex tetrahydropyran rings found in many natural products. In this new grant period we will investigate the stereoselectivity and regioselectivity of the segment-coupling Prins cyclization. A regioselective version of this reaction is the key step in a proposed synthesis of the natural product ratjadone. We will also develop two new oxacarbenium ion cyclizations: the Mukaiyama aldol-Prins (MAP) cyclization and the carbon-trapping Prins cyclizations. Simple versions of both of these new reactions have been demonstrated and presented in the progress report. The MAP reaction combines a Mukaiyama aldol reaction of alkyl enol ether with a Prins cyclization to produce two new carbon-carbon bonds, one new ring and several stereogenic centers. It is the basis for a proposed highly convergent synthesis of leucascandrolide A. The carbon-trapping Prins cyclization produces two new carbon-carbon bonds, one ring and several stereogenic centers. It is the basis of a proposed synthesis of epicalyxin F, an anticancer compound isolated from a traditional Chinese medicinal plant. These new methods will be powerful tools for the assembly of tetrahydropyran natural products. Each of the synthetic targets selected for investigation has antitumor activity. Phorboxazole B is clearly the most important because of its extreme potency and because of the dearth of naturally available material. However, the other synthetic targets, leucascandrolide A, epicalyxin F and ratjadone also have interesting antitumor activity, and these synthetic products will be made available to collaborators for evaluation.

该提案中的主要合成目标是高效抗癌剂苯并恶唑B。Phorboxazol B被用来对抗NCI的小组肿瘤细胞系，例如，被发现抑制结肠肿瘤细胞HCT-116的生长(GI50 4.36×10(-10)M)。在前一个授权期内，使用我们的链段偶联Prins环化反应制备了两个关键的呋喃唑环。合成的完成将通过组装大环内酯A和连接侧链B来完成。将向合作者提供合成的苯并恶唑，以评估其作用模式，并评估其作为抗癌剂的潜力。我们正在开发Prins环化反应，用于合成在许多天然产品中发现的复杂的四氢吡喃环。在这一新的授权期，我们将研究链段偶联Prins环化反应的立体选择性和区域选择性。该反应的区域选择性版本是合成天然产物雷吉酮的关键步骤。我们还将开发两个新的氧碳正离子环化反应：Mukaiyama Aldol-Prins(MAP)环化反应和碳捕获Prins环化反应。进度报告中演示并介绍了这两种新反应的简单版本。MAP反应结合了烷基烯醇醚的Mukaiyama Aldol反应和Prins环化反应，产生了两个新的碳-碳键，一个新的环和几个立体中心。碳捕获Prins环化反应产生两个新的碳-碳键，一个环和几个立体生成中心。它是从一种中药植物中分离出来的一种抗癌化合物Eicalysin F的拟议合成的基础。这些新方法将成为组装四氢吡喃天然产物的有力工具。选择用于研究的每个合成靶点都具有抗肿瘤活性。苯并恶唑B显然是最重要的，因为它具有极高的效力，而且由于缺乏天然可获得的材料。然而，其他合成靶标，亮氨酸内酯A，表儿茶素F和雷公藤酮也具有有趣的抗肿瘤活性，这些合成产品将提供给合作者进行评估。