新型喹唑啉酮类衍生物的设计、合成与体外抗肿瘤活性评价  

Novel Quinazolinone Derivatives:The Design,Synthesis and In vitro Antitumor Activity Evaluation

作　　者：赵灿 李志 马晓东 ZHAO Can;LI Zhi;MA Xiao-dong(College of Pharmacy,Anhui University of Chinese Medicine,Hefei 230012,China;Department of Medicinal Chemistry,Anhui Academy of Chinese Medicine,Hefei 230012,China)

机构地区：[1]安徽中医药大学药学院,安徽合肥230012 [2]安徽省中医药科学院药物化学研究所,安徽合肥230012

出　　处：《化学试剂》2023年第12期112-117,共6页Chemical Reagents

基　　金：安徽省自然科学基金面上项目(2208085MH280);安徽高校协同创新项目(GXXT-2022-063)。

摘　　要：为发现具有抗实体瘤活性的新型喹唑啉酮类衍生物,以2-氨基-6-氯苯甲酸为原料,经缩合、环合、亲核取代、脱Boc、芳族亲核取代以及羟胺解反应,得到3个目标分子,并通过1HNMR、13 CNMR以及HR-MS对其进行了结构确证。目标化合物的抗增殖活性测试结果表明,所有目标分子对PC-3、MDA-MB-231以及T-47D这3种实体瘤细胞株的增殖抑制活性均与阳性对照SAHA、Idelalisib相当或更优,且对正常细胞毒性较低。分子对接的结果,揭示了目标化合物与PI3Kδ蛋白以及HDAC蛋白的可能结合模式。This study aimed at the discovery of novel quinazolinone derivatives for battling solid tumors.Three target compounds were obtained through condensation,cyclization,nucleophilic substitution,Boc-deprotection,aromatic nucleophilic substitution,and hydroxylaminolysis reactions with 2-amino-6-chlorobenzoic acid as raw materials.Structural confirmations were achieved through 1HNMR,13 CNMR,and HR-MS analysis.The anti-proliferative assay demonstrated that all the target compounds exhibited comparable or superior activity to the positive control SAHA and Idelalisib against the three solid tumor cell lines(PC-3,MDA-MB-231,and T-47D),and low cytotoxicity towards normal cells.The results of molecular docking elucidate the possible binding mode of target compound with PI3Kδprotein and HDAC protein.

关 键 词：设计 合成 磷脂酰肌醇-3-激酶δ 组蛋白去乙酰化酶 抗增殖活性 

分 类 号：R914.5[医药卫生—药物化学]