SYNTHESIS OF ANTICANCER HELIANGOLIDES

抗癌姜内酯的合成

• 批准号: 3182418
• 负责人: DRURY S CAINE
• 金额: $ 4.93万
• 依托单位: UNIVERSITY OF ALABAMA IN TUSCALOOSA
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-08-01 至 1990-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3182418
• 关键词: alkylation; antineoplastics; carcinoma; drug design /synthesis /production; enolate; lactones; mannose; nasopharyngeal neoplasms; stereochemistry

This proposal is concerned with the study of a synthetic approach to the naturally occurring heliangolides ciliarin, budlein A, lychnophorolide A, and eremantholide A. Some of these compounds have been found to show significant activity against cells derived from human carcinoma of the nasopharynx (KB). All of these compounds but eremantholide A contain two electrophilic moieties, i.e., a double bond in conjugation with a 3(2H)-furanone ring and an alpha-methylene lactone, that are capable of covalent binding to nucleic acids and enzymes. The proposed approach involves alkylation of a chiral tetrahydrofuranone lithium enolate, obtainable from D-mannose, with a chiral gamma-lactone containing an iodoisprepenyl group at the beta-position and a protected hydroxymethyl group trans to it at the gamma-position. 1,3-Asymmetric induction should cause the alkylation product to have the correct stereochemistry at C- 6, C-7, and C-10 of the natural products. After appropriate transformations, the initial alkylation product should yield a molecule containing an iodomethyl group at the gamma-position of the lactone ring and a 3(2H)-furanone moiety convertible into a linearly conjugated dienolate upon deprotonation with a strong base. Cycloalkylation at the gamma-position of the dienolate should allow the closure of the ten-membered carbocyclic ring and the production of a product that upon ozonolysis of an exocyclic double bond would yield a ketone containing the heliangolide ring skeleton. Conversion of this system into the target natural products should be relatively straightforward although it involves several steps.

这项建议涉及研究一种综合办法， 到天然存在的向日葵内酯纤毛素，芽苞素A， lychnophortia A和eremanthtia A. 其中一些 已经发现化合物显示出显著的抗 来源于人鼻咽癌（KB）的细胞。 所有 这些化合物，但eremanthropa含有两个亲电 部分，即，与3（2 H）-呋喃酮共轭的双键 环和α-亚甲基内酯，其能够共价连接 与核酸和酶结合。 所提出的方法涉及手性 四氢呋喃酮烯醇化锂，可得自D-甘露糖， 与含有碘代异丙烯基的手性γ-内酯 在β-位上和一个被保护的羟甲基反式， 在gamma的位置。 1，3-不对称感应应导致 烷基化产物在C-位具有正确的立体化学， 6、C-7和C-10的天然产物。 经过适当 转化，初始烷基化产物应产生 在γ-位含有碘甲基的分子 内酯环和3（2 H）-呋喃酮部分可转化为 线性共轭二烯醇化物在去质子化时具有强的 基地 在二烯醇化物的γ-位的环烷基化 应该允许十元碳环闭合 以及在臭氧分解一种化合物时， 环外双键将产生含有 Heliangeling光环骨架. 将该系统转换为 目标天然产品应该相对简单 尽管它涉及几个步骤。