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）：这项研究的目的是开发向抗肿瘤剂孔甲中年蛋白E和D的立体控制路线，并从硫酸脂肪分析中分离出来的。在体外对鼠结肠26-L5癌细胞的活性最强，ED50为3.61 MuM。更重要的是，明显，珠甲状腺素表现出抑制性活性，对人类纤维肉瘤HT-1080细胞具有9.02 MU M的ED50的5-flu（在5-flu）中使用ED50的ED50，该细胞具有抑制性。 m）。为了利用这些新颖的抛脑蛋白阵列作为治疗人肿瘤的药物的全部潜力，计划了合成研究。这些类似物的绝对结构是基于多种光谱数据分配的，也是与先前的骨a。Blepharocalyx的分离株相比。但是，尚未通过总合成来验证这些结构分配。因此，这项研究很重要，原因有两个。除了确认这些天然产物的绝对结构外，通往这些化合物的大规模路线有望为筛选提供有用的类似物。 该提案的主体将集中于CIS融合的二氧化甲酸内酯（6,6-6-和6,5熔融）的立体选择性合成，并在立体控制的C- Aryl pyranosides的立体控制结构中通过环开替换反应。本练习的目的是开发有用的模型，以合成骨丙酰氧蛋白D和E。为6,5型融合的系统合成，Mn（LLL）乙酸乙酸乙酯甲基丙二这酯甲基丙二醇酸酯对二氢酯的自由基添加将被研究，同时将对杂型二氢酯进行研究，同时使用A Hetero-Diels-diels-alder-Alder-Alder-Alder-Alder-Alder-Alder-Ardude Serge segrets Adreg Sepred Sepred Sepred Sepred Sepred Sepred Sepred Sepreds 6,6,6,6,6,6-6-6-f。将首次研究两个双环内酯系列的原位产生。要测试的假设是，富含电子的芳族供体是否始终以β-选择性添加到这些氧化离子中间体中。