新型复合功能手性辐射防护剂的设计、合成及构效关系研究

Nuclear weapon, nuclear leakage, and clinical radiotherapy will result in ionizing radiation damage, even life-threatening. So it's necessary to provide high efficiency and low toxicity radioprotective drugs. More reports on radiation protection in recent years are about melatonin with indole nucleus , nitroxides radicals, sulfones and phenols. Two indole analogues are obtained from plants by applicant. Previous experimental results show that, they have comparatively radioprotective effects compared with melatonin. In our previous work,we developed a NIT type of nitroxide radicals, which could be used with a catalytic amount. And a nitroxide radical of L-NIT-2011 was obtained, whose radiation protective effect is better than that of the WR-2721. The project will use chiral L-NIT-2011 as the leading compound. Based on the theory of antioxidant complex chain and the method of dual target drug design, all structures were synthesized by combination of the leading compounds with sulfones structure (targeting on the cell membrane), phenolic structure (removing harmful free radicals quickly) or melatonin analogues. The pharmacological experiments, structure-activity relationship and preliminary mechanism of the target compound will be carried out in vivo and in vitro. The aim of the study is to obtain a novel radioprotector with features of catalytic amount, high efficiency and low toxicity, providing theoretical basis and experimental data for the development of new radiation protectors.

核武器爆炸、核设施泄漏及临床放射治疗都会引起电离辐射损伤，重者危及生命。迫切需要高效低毒的防护药物。近年辐射防护报道较多的是以吲哚环为母核的melatonin、氮氧自由基、砜类和酚类物质。申请者从植物中分离到两个吲哚衍生物，实验结果显示辐射防护作用与melatonin相当；课题组还发现一类具有可"催化量"发挥作用的NIT类氮氧自由基，获得了一个药效超过目前公认的WR-2721的结构L-NIT-2011。本项目以手性L-NIT-2011为先导物，依据"抗氧化剂复合链"理论及"双靶标药物设计"原理，将作用于细胞膜发挥作用的砜类结构、快速清除有害自由基的酚类结构以及吲哚衍生物分别与先导物母核巧妙结合，构建系列具有复合功能的辐射防护剂结构，并进行体内外药理作用、构效关系及初步作用机理研究；以期筛选出高效低毒"可催化量"发挥作用的新型辐射防护剂结构，为新型辐射防护剂的研究提供理论依据和实验数据。

临床放射治疗、核泄漏事件和核武器都会引起电离辐射损伤，重者危及生命。本项目依据“抗氧化剂复合链”理论及“双靶标药物设计”原理在前期工作基础上合成一系列新型氮氧自由基结构并考察其抗辐射生物学活性。主要完成内容：一、改进了关键中间体二羟胺的合成方法，设计、合成了12个新型氮氧自由基分子，纯化并表征其结构；二、考察上述分子的辐射防护性能，评价目标分子对经辐射后的细胞和小鼠的保护作用，探讨此类化合物辐射防护的分子机制，筛选出高活性的辐射防护剂结构；三、考察氮氧自由基的次声防护性能，评价目标分子对由次声暴露引起的大鼠海马神经元损伤的保护作用，以及改善由次声暴露诱导的学习和记忆障碍，探讨此类化合物防护次声损伤的抗氧化机制，筛选出高活性的次声损伤防护剂结构；考察部分氮氧自由基的抗肿瘤活性。取得的成绩：发表国外SCI文章7篇，培养研究生3名，申请专利2项，获得专利1项并获陕西省科技进步一等奖1项。