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: 3875833
• 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/3875833
• 关键词: Plasmodium falciparum; X ray crystallography; alcohols; antimalarial agents; carbonyl group; chemical structure; chemical structure function; chemical synthesis; conformation; drug design /synthesis /production; folk medicine; hydroxyl group; malaria; malaria vaccines; medicinal plants; methylcholanthrene; molecular asymmetry; nuclear magnetic resonance spectroscopy; oxetane; peroxides; photochemistry

The formidable problems encountered in developing a malaria vaccine, and the ability of Plasmodium falciparum to become resistant to new drugs, have stimulated interest in using combinations of drugs for treating this disease, which claims more than a million lives a year. One drug of current interest, artemisinin, was isolated by Chinese investigators from a traditional medicinal herb. Esters and ethers of dihydroartemisinin have been prepared by several groups for structure-activity studies of their antimalarial properties. These demonstrated that the peroxide bridge was required for pharmacological activity. In order to increase the functionality of the molecule, we investigated the ability of the fungus Beauveria sulfurescens to introduce a hydroxyl group into the N-phenyl urethane of dihydroartemisinin. Two products were isolated from these studies. One was shown by (1)H, (13)C and 2D nmr studies to contain a new hydroxyl group, present as a hydroxymethyl, and still had intact the peroxide group required for biological activity. The structure of the second product was also determined by nmr and it was found to have been formed by a rearrangement of the peroxide group. A variety of derivatives of the first compound will be prepared and tested for their activity against cerebral malaria.

在研制疟疾疫苗时遇到的困难， 恶性疟原虫对新药产生抗药性的能力， 刺激了使用药物组合来治疗这种疾病的兴趣， 这种疾病每年夺去100多万人的生命。目前的一种药物 中国研究人员从一种名为“青蒿素”的植物中分离出了一种令人感兴趣的物质， 双氢青蒿素的酯和醚具有 由几个小组制备，用于其结构活性研究， 抗疟疾特性。这表明过氧化物桥是 药理活性所需。为了增加 分子的功能，我们研究了真菌的能力， 通过在N-苯基上引入羟基， 双氢青蒿素尿烷从中分离出两种产物 问题研究其中一个经（1H）、（13）C和2D NMR研究表明含有一个新的 羟基，作为羟甲基存在，并且仍然具有完整的 生物活性所需的过氧化物基团。的结构 还通过NMR测定了第二种产物，并发现其 通过过氧化物基团的重排形成。多种衍生物 将制备第一种化合物并测试其活性 对抗脑型疟疾