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phorboxazole B，这是一种非常有效的抗癌剂。对NCI面板肿瘤细胞系进行了测试，例如，发现抑制结肠肿瘤细胞HCT-116（GI50 4.36 x 10（-10）M）的生长。 phorboxazole的两个关键段是在上一个赠款期间使用我们的段耦合Prins环化制备的。综合的完成将通过大花环A组装并连接侧链b来完成。合成phorboxazole将提供给合作者评估其作用方式，并评估其作为抗癌剂的潜力。我们正在开发Prins环化，以合成许多天然产物中发现的复杂四氢吡喃环。在这个新的赠款期间，我们将研究节耦合Prins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提议合成天然产物Ratjadone的关键步骤。我们还将开发两个新的oxaCarbenium离子环化：Mukaiyama Aldol-Prins（MAP）环化和碳捕获Prins循环。这两种新反应的简单版本已在进度报告中证明和介绍。该地图反应结合了烷基烯醇醚与Prins环化的mukaiyama aldol反应，以产生两个新的碳碳键，一个新的环和几个立体基因中心。它是提议高度收敛合成的Leucascandrolide A的基础A。碳捕集的Prins环化产生了两个新的碳碳键，一个环和几个立体生成中心。它是提议合成epicalyxin f的基础，这是一种从传统的中国药用植物中分离出来的抗癌化合物。这些新方法将是四氢吡喃天然产品组装的强大工具。选择用于研究的每个合成靶标具有抗肿瘤活性。 phorboxazole B显然是最重要的，因为它具有极高的效力和自然可用的材料的缺乏。然而，其他合成靶标，leucascandrolide A，epecicalyxin F和ratjadone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。