Synthesis of Anticancer Agents Using Prins Cyclizations

使用 Prins 环化合成抗癌剂

• 批准号: 6619600
• 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/6619600
• 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.

本方案的主要合成靶点是一种非常有效的抗癌剂——磷恶唑B。对Phorboxazole B对NCI的肿瘤细胞系进行了实验，发现它可以抑制结肠肿瘤细胞HCT-116 （GI50 4.36 X 10(-10) M）的生长。phoboxazole的两个关键片段是在之前的资助期内使用我们的片段偶联Prins环化制备的。通过组装大环内酯A并连接侧链B来完成合成。合成的磷唑将提供给合作者，以评估其作用方式，并评估其作为抗癌剂的潜力。我们正在开发普林斯环化，用于合成在许多天然产物中发现的复杂的四氢吡喃环。在这个新的资助期，我们将研究节段耦合普林斯环化的立体选择性和区域选择性。该反应的区域选择性版本是天然产物ratjadone合成的关键步骤。我们还将开发两种新的氧碳离子环化：Mukaiyama aldo -Prins （MAP）环化和碳捕获Prins环化。这两种新反应的简单版本已在进度报告中得到演示和介绍。MAP反应结合了烷基烯醇醚的Mukaiyama醛醇反应和普林斯环化反应，生成两个新的碳-碳键、一个新的环和几个立体中心。这是提出的高收敛合成亮色木质素a的基础。碳捕获普林斯环化产生两个新的碳-碳键，一个环和几个立体中心。它是从一种传统的中草药植物中分离出来的抗癌化合物epicalyxin F的合成基础。这些新方法将为四氢吡喃天然产物的合成提供有力的工具。所选择的每一个合成靶点都具有抗肿瘤活性。磷唑唑B显然是最重要的，因为它具有极强的效力，而且缺乏天然可用的材料。然而，其他的合成靶点，亮子candrolide A， epicalyxin F和ratjadone也有有趣的抗肿瘤活性，这些合成产物将提供给合作者进行评估。