Condensations and Cyclizations to Bioactive Heterocycles

缩合和环化为生物活性杂环

• 批准号: 6525922
• 负责人: JON Douglas RAINIER
• 金额: $ 18.94万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6525922
• 关键词: alkaloids; alkyl nitrile; alkynes; antimitotics; biological products; chemical condensation; chemical synthesis; cyclization; free radicals; indoles; neurotransmitter antagonist

DESCRIPTION: (Applicant's Descripiton) The isolation of biologically interesting natural products from sensitive sources continues to be one of the best ways of finding medicinally relevant lead compounds. Unfortunately, we are usually unable to isolate sufficient quantitites of many of these bioactive compounds for their full evaluation. Outlined herein are our plans to improve this situation through the synthesis of the bioactive natural products spirotryprostatin A spirotryprostatin B, and voachalotine. Also included are the description of new and improved (more efficient) synthetic techniques. The synthesis of the agents described in this proposal will not only provide quantities of materials that are not currently available but it is only through these efforts that we can begin to understand their important biological activity. The spirotryprostatins are members of the spiro-oxindole family of natural products isolated from Aspergillus fumigatus. They have demonstrated the ability to inhibit the mammalian cell cycle at the G2/M phase at the micromolar level and are therefore potential antineoplastic leads. Voachalotine is a spiro-fused oxindole alkaloid isolated from Voacanga chalotiana. Related compounds have demonstrated short term inhibitory activity of ganglionic transmission. In addition to synthesis efforts toward the agents mentioned above, we intend to answer several important questions related to organic chemistry methodology during the time period of this proposal. First, can we expand on our isonitrile-alkyne free-radical coupling chemistry to generate substituted indoles? Second, can we utilize thioamide-alkyne free-radical couplings to substituted indoles? Third, can we develop novel approaches to the asymmetric synthesis of substituted indoles?

描述：(申请者的描述)从生物学上分离 来自敏感来源的有趣天然产品继续是 寻找与医学相关的先导化合物的最佳方法。不幸的是，我们是 通常无法分离出足够数量的这些生物活性物质 对化合物进行全面评估。这里概述的是我们的改进计划 这种情况通过合成具有生物活性的天然产物来实现 安非他明A、安非他明B和伏沙罗汀。此外，还包括 对新的和改进的(更有效的)合成技术的描述。这个 本提案中所描述的试剂的合成不仅将提供 当前不可用的材料数量，但仅通过 这些努力使我们能够开始了解它们重要的生物学特性 活动。 螺旋前列腺素是天然的螺氧吲哚家族的成员。 从烟曲霉中分离出的产物。他们已经证明了 在微摩尔水平抑制哺乳动物细胞周期于G2/M期的能力 水平，因此是潜在的抗肿瘤线索。 Voachalotine是从Voacanga中分离得到的螺环稠合氧吲哚生物碱 查洛蒂亚纳。相关化合物显示出短期抑制活性。 神经节传播性疾病。 除了针对上述试剂的合成努力外，我们还打算 回答与有机化学方法论有关的几个重要问题 在本提案的时间段内。首先，我们可以扩展一下我们的 异腈-炔烃自由基偶联化学生成取代基 吲哚？第二，我们能否利用硫代酰胺-炔基自由基偶联来 取代吲哚？第三，我们能否开发新的方法来应对不对称 取代吲哚的合成？