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）生物学上的隔离 来自敏感来源的有趣的天然产品仍然是 寻找与药物相关的铅化合物的最佳方法。不幸的是，我们是 通常无法隔离许多此类生物活性的足够定量材料 具有完整评估的化合物。此处概述的是我们改进的计划 通过合成生物活性天然产品的这种情况 螺旋形蛋白A螺旋杆蛋白B和voachalotine。还包括 新的和改进（更有效）合成技术的描述。这 本提案中描述的代理的合成不仅将提供 数量目前尚不可用的材料，但仅通过 我们可以开始理解它们重要的生物学的这些努力 活动。 SpirotryProstatins是天然的Spiro-Oxindole家族的成员 从曲霉菌分离的产品。他们已经证明了 能够在微摩尔处抑制G2/m相处的哺乳动物细胞周期 水平，因此是潜在的抗塑性铅。 Voachalotine是一种从伏安加（Voacanga Chalotiana。相关化合物已显示出短期抑制活性 神经节传输。 除了对上述代理的合成努力外，我们还打算 回答与有机化学方法有关的几个重要问题 在此提案的期间。首先，我们可以扩展我们的 异构体 - 阿尔基（Isonisrile-Alkyne）自由基耦合化学反应以产生取代 吲哚？其次，我们可以利用硫酰胺 - 阿尔基（Thioamide-Alkyne）自由基耦合 取代吲哚？第三，我们可以开发新的方法 取代吲哚的合成？