STEREOSELECTIVE SYNTHESIS OF FOSTRIECIN ANALOGS

磷霉素类似物的立体选择性合成

• 批准号: 6514903
• 负责人: BROCK T SHIREMAN
• 金额: $ 3.83万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-26 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6514903
• 关键词: antineoplastic antibiotics; chemical synthesis; drug design /synthesis /production; molecular rearrangement; phosphodiesterase inhibitors; silicon; stereochemistry; stereoisomer

The initial goal of the proposal is the development of an enantioselective hypervalent silicon mediated acyloin rearrangement (1 to 2) utilizing chiral ureas to promote the reaction. Upon realization of the first goal, the total synthesis of novel analog 3 of the selective phosphodiesterase 2 a (PP2a) inhibitors, fostriecin (IC50=40 Nm) and phoslactomycin F (ic50=4,7 muM) will be pursued utilizing the proposed methodology. The inhibition of PP2a has been reported to account for the potent anti-tumor activity of fastriecin against leukemia cells (I50=0.46 muM). The synthesis of 3 would provide insight into the differences in biological activities of the parent compounds, fostriecin, the phoslactomycins, and the leustroducsins. While this proposal will focus on the synthesis of analog 3, the synthesis is flexible thus allowing for future total syntheses of the parent natural products in addition to other analogs.

该提案的最初目标是利用手性脲促进反应的对映选择性高价硅介导的丙环蛋白重排（1到2）的发展。在实现第一个目标后，将利用所提出的方法进行选择性磷酸二酯酶2a （PP2a）抑制剂，fostriecin （IC50=40 Nm）和phoslactomycin F （IC50= 4,7 muM）的新型类似物3的全合成。据报道，抑制PP2a是fastriecin对白血病细胞有效的抗肿瘤活性的原因（I50=0.46 muM）。3的合成将有助于深入了解亲本化合物fostriecin、phoslactomycin和leustroducsin的生物活性差异。虽然本提案将重点放在类似物3的合成上，但该合成是灵活的，因此除了其他类似物外，还允许将来对母体天然产物进行全合成。