二苯甲酰甲烷类卤酚的合成、活性评价及与CAV-1的相互作用  

Synthesis,bioactivity evaluation of dibenzoyl methane halophenols and their interactions with CAV-1

作　　者：刘恒江 程宁宁 张梦如 原红霞 张圆琳 冯秀娥[1] 李青山[1,2] LIU Heng-jiang;CHENG Ning-ning;ZHANG Meng-ru;YUAN Hong-xia;ZHANG Yuan-lin;FENG Xiu-e;LI Qing-shan(School of Pharmaceutical Science,Shanxi Medical University,Taiyuan 030001,China;Shanxi Key Laboratory of Innovative Drug for the Treatment of Serious Diseases Basing on the Chronic Inflammation,Shanxi University of Chinese Medicine,Jinzhong 030619,China)

机构地区：[1]山西医科大学药学院,山西太原030001 [2]山西中医药大学,基于炎性反应的重大疾病创新药物山西省重点实验室,山西晋中030619

出　　处：《药学学报》2021年第12期3493-3502,共10页Acta Pharmaceutica Sinica

基　　金：重大新药创制国家科技重大专项(2018ZX09711001-001-017);山西省重点研发计划(重点)项目(201703D111033);山西省自然科学基金资助项目(201901D111209)。

摘　　要：小窝蛋白-1(CAV-1)与炎症、氧化损伤、免疫密切相关。为了获得靶向CAV-1且具有强抗炎抗氧化作用的二苯甲酰甲烷类卤酚,本文以不同基团取代的酰氯与邻羟基苯乙酮为起始原料,经Baker-ventaraman重排、脱甲基反应合成了29个目标卤酚,并采用生物膜干涉(BLI)技术,定量研究其与CAV-1的相互作用,同时评价其体外抗炎和抗氧化作用。结果表明,化合物A6、A17、A18、A29既与CAV-1有特异性结合,又具有很强的抗炎和抗氧化作用,这些化合物可能是通过直接作用于CAV-1,进而影响炎症和氧化应激相关的信号通路。尤其是,该类化合物对IL-1β和COX-2的抑制作用最为显著,而IL-1β是关节炎发生环节的关键调控角色。因此,该类化合物可能在防治关节炎方面有重要的应用前景。Caveolin-1(CAV-1)is related to inflammation,oxidative damage,and immunity.In order to obtain a series of dibenzoylmethane halophenols with strong anti-inflammatory and antioxidant effects targeting CAV-1,twenty-nine target compounds were therefore synthesized by Baker-Ventaraman rearrangement and demethylation reaction,starting from the substituted benzoyl chloride and o-hydroxyacetophenone,and their interactions with CAV-1 were investigated by BLI technique.Their in vitro anti-inflammatory and antioxidant properties were also evaluated.The results showed that compounds A6,A17,A18,and A29 not only specifically bind to CAV-1,but also present strong anti-inflammatory and antioxidant effects.These results suggest that this class of compounds can affect the signaling pathways related to inflammation and oxidative stress by directly acting on CAV-1.In particular,these compounds exhibit the most significantly inhibitory effects on IL-1βand COX-2 release.IL-1βplays a key regulatory role in the development of arthritis.Therefore,it is worth expecting for the application of such compounds in the prevention and treatment of arthritis.

关 键 词：二苯甲酰甲烷 合成 小窝蛋白-1 抗炎 抗氧化 

分 类 号：R914[医药卫生—药物化学]