具有新作用机制的芳环衍生物LPA2受体激动剂设计、合成及抗辐射构效关系研究

Since entering the nuclear age, people are confronted with the increasing probability of nuclear radiation damage, therefore, anti-radiation drugs play increasingly significant roles. As for strategic reserve drugs and military equipment drugs, the disadvantages of drugs are as followed: severe side-effects, poor stability, and low efficacy, thus requiring to develop novel anti-radiation agents. Hemolysis phosphate (LPA) is a growth factor like lipid mediators, LPA2 receptor agonists DBIBB can enhance DNA repair capacity and significantly improve the survival rate of mice irradiated by a lethal dose of δ- ray, and both before and after the irradiation administration ensures valid results, which is used for the treatment of bone marrow and gastrointestinal-type acute radiation sickness, but Leukogenic effects are less obvious. Since DBIBB and P53 inhibitors PFTα have similar structures, the side chain of P53 inhibitors is introduced in the existing leukogenic groups, a new kind of structure of LPA2 receptor agonist is planed to designed. Biological activity evaluation shows Preferred compounds have good anti-radiation activity, and leukogenic effect, which lays foundations for the research of new anti-radiation drugs.

随着我国核能工业、核技术的开发与广泛应用，人类面临的核辐射损伤几率加大，抗辐射药研究具有越来越重要的意义。已有抗辐射药物存在副作用大、疗效低等缺点，这与其作用机制、靶标与辐射敏感相关性低密切相关，因此需要研发新作用机制或靶标的抗辐射药物。溶血磷酸脂LPA是一种生长因子样脂类介质，LPA2受体激动剂DBIBB能增强DNA修复能力，显著提高受致死剂量的γ-射线照射小鼠的存活率，且照前照后给药均有效，但用于治疗急性放射病时，不能明显升高白细胞水平，不利于骨髓型放射病的治疗与康复。已知DBIBB与P53抑制剂PFTα结构具有相似性，尝试在现有的升白基团如“茜草双酯基”引入P53抑制剂的侧链，拟设计一类新结构LPA2受体激动剂，生物活性评价表明优选化合物具有较好的抗辐射活性，且有明显的升白作用，其作用机制不同DBIBB，这对发现新药理作用机制的高效、低毒辐射防护剂具有重要意义。

LPAR2受体激动剂DBIBB与P53抑制剂PFTα均具有细胞保护作用，其结构分为阴离子头部、疏水连接部、芳香尾部。二者结构具有相似性，提示DBIBB连接基可以用芳基替代。本课题针对DBIBB本身无明显的血象改变（升白作用）的缺点，将其头部以升白基团替换，连接部保留疏水的四碳链状基团或以疏水的芳环进行替换，尾部以羧酸及其衍生物替代进行改造。设计、合成了3个系列化合物39个。其中12个化合物抗辐射活性优于或与DBIBB相当。构效关系研究表明将先导化合物DBIBB的连接基团氨磺酰基替换为酰胺基同时在头部羧酸间位引入溴原子，其尾部1,8-萘二甲酰亚胺简化为保留有疏水性、芳香性和π-π相互作用的（E）-4-（丙-1-烯-1-基）苯酚，其细胞存活率在预防给药和治疗给药时均有明显提高，抗辐射活性显著增强。为本课题深入研究奠定了坚实的基础。