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）：本研究的目的是开发立体控制的抗肿瘤药物blepharocalyxin E和D的途径。这些天然产物是从眼萼山姜中分离出来的，它们作为治疗人类肿瘤的潜在候选药物显示出了特别的前景。Blepharocalyxin D在体外对小鼠结肠26-L5癌细胞显示出最强的活性，ED 50为3.61 μ M。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，ED 50为9.02 μ M，其活性与临床使用的5-氟尿嘧啶（ED 50为8.00 μ M）相当。为了开发这些新的眼睑萼蛋白阵列作为治疗人类肿瘤的试剂的全部潜力，计划进行合成研究。根据各种光谱数据，并通过与以前分离的A.眼睑萼然而，通过全合成这些结构归属的验证还没有报道。这项研究之所以重要，主要有两个原因。除了确认这些天然产物的绝对结构外，这些化合物的大规模路线将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，以及随后通过开环取代反应在C-芳基吡喃糖苷的立体控制构建中的应用。这项工作的目的是开发有用的模型，用于合成眼睑萼素D和E。对于6，5-稠合体系的合成，将研究Mn（III）乙酸盐介导的甲基丙二酸钾酯与二氢吡喃的自由基加成，而杂-Diels-桤木途径将用于制备相应的6，6-稠合体系。原位生成的oxocarbenium离子从双环内酯系列将首次进行研究。待测试的假设是富电子芳族供体是否始终以β-选择性添加到这些氧代碳鎓离子中间体中。