Condensations and Cyclizations to Bioactive Heterocycles

缩合和环化为生物活性杂环

• 批准号: 6326362
• 负责人: JON Douglas RAINIER
• 金额: $ 18.94万
• 依托单位: UNIVERSITY OF ARIZONA
• 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 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6326362
• 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：（申请人的描述） 来自敏感来源的有趣的天然产品仍然是 寻找与医学相关的先导化合物的最佳途径。不幸的是， 通常不能分离足够数量的这些生物活性物质 化合物进行全面评估。本文概述了我们的计划，以改善 这种情况通过生物活性天然产物的合成 螺曲前列腺素A、螺曲前列腺素B和伏查洛汀。还包括 新的和改进的（更有效的）合成技术的描述。的 本提案中描述的试剂的合成将不仅提供 目前无法获得的材料数量，但只能通过 这些努力使我们开始了解它们重要的生物学特性 活动 螺环前列腺素是天然药物螺环-羟吲哚家族的成员。 从烟曲霉中分离的产物。他们证明了 在微摩尔浓度下抑制哺乳动物细胞周期处于G2/M期的能力 水平，因此是潜在的领导者。 Voachalotine是从Voacanga中分离出的螺稠合羟吲哚生物碱 chalotiana。相关化合物已证明具有短期抑制活性 神经节传递的证据 除了对上述试剂的合成努力外，我们还打算 回答有机化学方法学中的几个重要问题 在此期间，该提案。首先，我们可以扩展我们的 异腈-炔自由基偶联化学以产生取代的 吲哚？第二，我们能否利用硫代酰胺-炔自由基偶联来 取代吲哚？第三，我们能否开发新的方法来解决不对称问题， 取代吲哚的合成