SYNTHESIS OF POLYETHER ANTIBIOTICS/MONENSIN ANALOGS

聚醚抗生素/莫能菌素类似物的合成

• 批准号: 2180134
• 负责人: ROBERT E IRELAND
• 金额: $ 22.61万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-04-01 至 1996-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2180134
• 关键词: analog; antibiotics; cardiotonic agents; chelating agents; chemical structure function; drug adverse effect; drug design /synthesis /production; drug screening /evaluation; ionophores; monensin

It is the goal of this program to develop efficient, practical (within the context of the complexity of the molecules involved) syntheses of the polyether ionophores. These antibiotics function as agents for ion/amine transport and through their ability to facilitate the transport of biologically relevant ions (Na+, K+, CA2+, etc.) or amines have the capacity to alter significantly cell metabolism. Commercially valuable as coccidiostats and anabolic agents, the polyether antibiotics are also proven cardiotonic agents. Therapeutic utilization of the ionophores as human cardiotonic agents is, however, severely limited by their toxicity and residual character that prevents effective dose regimes. Access to related chemical structures that still retain the ability to chelate metal ions/amines reversibly, but can overcome some of the toxicity and metabolic stability problems associated with the natural products may lead to useful therapeutic agents. It is the purpose of this effort to develop technology that can be generally applied to the synthesis of the characteristic polyether structure and design analogs of these ionophores that through biological testing will help define the requisite structural parameters for activity. Initial targets for the synthetic methodology part of the work are monensin and nigericin and then analogs related to these antibiotics will be prepared by that technology.

该计划的目标是开发高效、实用(在 所涉及的分子的复杂性的上下文)合成 聚醚离子载体。这些抗生素可作为离子/胺的试剂。 运输和通过其便利运输的能力 与生物有关的离子(Na+、K+、Ca2+等)或者说胺有 显著改变细胞新陈代谢的能力。有商业价值 作为球虫药和合成代谢剂，聚醚抗生素也是 经过验证的强心剂。离子载体在治疗中的应用 然而，人类强心剂受到其毒性的严重限制。 以及阻止有效剂量制度的残留性。进入 相关的化学结构仍然保持着螯合能力 金属离子/胺可逆，但可以克服一些毒性和 与天然产品相关的代谢稳定性问题可能 导致有用的治疗剂。这项努力的目的是 开发可普遍应用于合成的技术 这些离子载体的特征聚醚结构和设计类似物 通过生物测试将有助于定义必要的结构 活动的参数。综合方法论的初始目标 部分工作是莫能菌素和黑曲霉素类，然后是与 这些抗生素将通过这种技术来制备。