Synthetic Approaches to Blepharocalyxins D and E

眼睑萼蛋白 D 和 E 的合成方法

• 批准号: 6666077
• 负责人: KEITH Thomas MEAD
• 金额: $ 13.83万
• 依托单位: MISSISSIPPI STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-15 至 2006-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6666077
• 关键词: Diels Alder reaction; analog; antineoplastics; bicyclic compound; biological products; biotechnology; biotherapeutic agent; chemical structure function; chemical substitution; drug design /synthesis /production; drug screening /evaluation; flavonoids; lactones; method development; organic chemicals; plant extracts; stereochemistry

DESCRIPTION (provided by applicant): The goal of this research is to develop stereocontrolled routes to the antitumor agents blepharocalyxin E and D. Isolated from Alpinia blepharocalyx, these natural products have shown particular promise as potential drug candidates for the treatment of human tumors. Blepharocalyxin D showed the strongest activity against murine colon 26-L5 carcinoma cells in vitro, with an ED50 of 3.61 mu M. Even more significant, blepharocalyxin E displayed inhibitory activity towards human fibrosarcoma HT-1080 cells with an ED50 of 9.02 mu M, which is comparable in activity to the clinically used 5-fluorouracil (ED50 of 8.00 mu M). In order to exploit the full potential of these novel blepharocalyxin arrays as agents for the treatment of human tumors, synthetic studies are planned. The absolute structures of these analogues were assigned based on a variety of spectroscopic data, and also by comparison with previous isolates of A. blepharocalyx. However, a validation of these structure assignments through total synthesis has not been reported. This research, then, is important for two main reasons. In addition to confirming the absolute structures of these natural products, large-scale routes to these compounds would hopefully provide useful analogues for screening. The main body of this proposal will focus on the stereoselective synthesis of cis-fused dioxabicyclic lactones (6,6- and 6,5-fused) and their subsequent use, through ring opening substitution reactions, in the stereocontrolled construction of C-aryl pyranosides. The purpose of this exercise will be to develop useful models for the synthesis of blepharocalyxins D and E. For the synthesis of the 6,5-fused systems, Mn(lll) acetate mediated radical additions of potassium methyl malonate esters to dihydropyrans will be investigated, while a hetero-Diels-Alder route will used to prepare the corresponding 6,6-fused systems. The in situ generation of oxocarbenium ions from both bicyclic lactone series will be studied for the first time. A postulate to be tested is whether electron-rich aromatic donors consistently add to these oxocarbenium ion intermediates with beta-selectivity.

描述（由申请人提供）：本研究的目标是开发抗肿瘤药物 blepharocalyxin E 和 D 的立体控制途径。这些天然产物从 Alpinia blepharocalyx 中分离出来，作为治疗人类肿瘤的潜在候选药物表现出了特别的前景。眼睑萼素 D 在体外对小鼠结肠 26-L5 癌细胞表现出最强的活性，ED50 为 3.61 μM。更重要的是，眼睑萼素 E 对人纤维肉瘤 HT-1080 细胞显示出抑制活性，ED50 为 9.02 μM，活性与临床使用的5-氟尿嘧啶相当（ED50为8.00μ米）。为了充分利用这些新型眼睑萼蛋白阵列作为治疗人类肿瘤的药物的潜力，计划进行综合研究。这些类似物的绝对结构是根据各种光谱数据确定的，并且还通过与 A. blepharocalyx 的先前分离株进行比较来确定。然而，尚未报道通过全合成验证这些结构分配。这项研究之所以重要有两个主要原因。除了确认这些天然产物的绝对结构之外，这些化合物的大规模路线有望为筛选提供有用的类似物。 该提案的主体将重点关注顺式稠合二氧杂双环内酯（6,6-和6,5-稠合）的立体选择性合成及其随后通过开环取代反应在C-芳基吡喃糖苷的立体控制结构中的应用。本练习的目的是开发用于合成 blepharocalyxins D 和 E 的有用模型。为了合成 6,5-稠合系统，将研究乙酸 Mn(III) 介导的甲基丙二酸钾酯与二氢吡喃的自由基加成反应，而杂-Diels-Alder路线将用于制备相应的6,6-稠合系统。将首次研究从两个双环内酯系列原位生成氧碳鎓离子。要测试的假设是富电子芳香族供体是否始终以β选择性添加到这些氧碳鎓离子中间体中。