ASYMMETRIC SYNTHESIS--STRUCTURE, STEREOCHEMISTRY AND NMR

不对称合成——结构、立体化学和核磁共振

• 批准号: 6161927
• 负责人: H ZIFFER
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6161927
• 关键词: antimalarial agents; autoradiography; chemical structure function; chemical substitution; drug design /synthesis /production; drug interactions; molecular asymmetry; nerve /myelin protein; neurotoxicology; nuclear magnetic resonance spectroscopy; sesquiterpenes; stereochemistry

A new route for the synthesis of N-substituted 11-aza-artemisinins, 1, was developed with 11-azaartemisinin, 2, as the starting material. In the course of optimizing reaction conditions for the preparation of 2 an unexpected product was isolated and its structure determined to be a cyclohexanone derivative Posner et al. Had isolated cyclohexanone analogs in their studies of the mechanism of action of artemisinin analogs and reported that they exhibited antimalarial activity. As part of our collaboration with Professor Meshnick on the mechanism of action of artemisinin derivatives and their in vitro and in vivo neurotoxicity, we prepared [3H]-dihydroartemisinin. Professor Meshnick and associates found that arteether and dihydroartemisinin caused acute neuronal necrosis in specific areas of the brain, especially the vestibular nuclei and red nuclei. Autoradiograms on SDS gels run from [3H]-dihydroartemisinin treated cells, showed that four neuronal proteins of molecular weights 27, 32, 40 and 81 kDa had reacted with dihydroartemisinin. The doses required to react with these proteins were 5,000 times the therapeutic dose.

N-取代的11-氮杂-青蒿素的合成新路线，1， 以11-氮杂青蒿素2为起始原料研制而成。 在 制备2的反应条件优化过程 分离出意想不到的产物，其结构确定为 环己酮衍生物 Posner 等人。已分离出环己酮 青蒿素作用机制研究中的类似物 类似物并报道它们具有抗疟活性。 作为 我们与 Meshnick 教授合作研究机制的一部分 青蒿素衍生物及其体内外作用 神经毒性，我们制备了[3H]-二氢青蒿素。 梅什尼克教授 和同事发现蒿乙醚和二氢青蒿素可引起急性 大脑特定区域的神经元坏死，尤其是 前庭核和红核。 SDS 凝胶上的放射自显影图来自 [3H]-二氢青蒿素处理的细胞显示，四个神经元 分子量为 27、32、40 和 81 kDa 的蛋白质与 双氢青蒿素。 与这些蛋白质发生反应所需的剂量 是治疗剂量的5000倍。