二苯甲酮类多酚的糖基化衍生、活性评价及与PDIA6的相互作用  

Glycosylation derivatization,bioactivity evaluation of benzophenone polyphenols and their interaction with protein disulfide isomerase A6

作　　者：李蔷 程宁宁 冯秀娥[1,2] 李青山[1,2,3] LI Qiang;CHENG Ning-ning;FENG Xiu-e;LI Qing-shan(School of Pharmaceutical Science,Shanxi Medical University,Taiyuan 030001,China;Medicinal Basic Research Innovation Center of Chronic Kidney Disease,Ministry of Education,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]山西医科大学,教育部慢性肾脏病医药基础研究创新中心,山西太原030001 [3]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》2024年第6期1706-1719,共14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项目(202102130501005);山西省自然科学基金项目(201901D111209);基于炎性反应的重大疾病创新药物山西省重点实验室2021年度开放课题(2021sxcxyw06).

摘　　要：蛋白质二硫键异构酶A6(PDIA6)与炎症和内质网应激密切相关。为了获得靶向PDIA6且具有强抗炎作用的二苯甲酮类多酚糖基衍生物,本文以不同基团取代的二苯甲酮与α-溴代乙酰糖为起始原料,经傅克酰基化、脱乙酰基反应合成了25个目标糖基衍生物,并采用生物膜干涉(BLI)技术,定量研究其与PDIA6的相互作用,同时评价其体外抗炎作用。结果表明,化合物4b、10b、17b、18b、25b既与PDIA6有较高的亲和力,又具有很强的抗炎作用,这些化合物可能是通过直接作用于PDIA6,进而影响炎症相关的信号通路。尤其是,该类化合物对IL-1β和IL-6的抑制作用最为显著,推测其在治疗炎症性疾病方面有重要的开发前景。Protein disulfide isomerase A6(PDIA6)is closely related to inflammation and endoplasmic reticulum stress.To obtain the glycosyl derivatives of benzophenone polyphenols targeting PDIA6 with strong antiinflammatory effects,twenty-five target glycosyl derivatives were synthesized by Friedel-Crafts acylation and deacetylation reaction,starting from the substituted benzophenone andα-bromoacetyl saccharide,and their interactions with PDIA6 were quantitatively investigated by bio-layer interferometry(BLI)technique.Their in vitro anti-inflammatory properties were also evaluated.The results showed that target compounds 4b,10b,17b,18b,and 25b not only exhibit high affinity with PDIA6,but also present strong anti-inflammatory abilities.Above results suggest that this class of compounds can affect the signaling pathways related to inflammation by directly acting on PDIA6.In particular,such compounds exhibit the strong inhibitory effects on IL-1βand IL-6 release,suggesting the potential development prospect in the treatment of inflammatory diseases.

关 键 词：二苯甲酮类多酚 合成 糖基化 蛋白质二硫键异构酶A6 抗炎 

分 类 号：R914[医药卫生—药物化学]