邻苯甲酰磺酰亚胺类HDACs抑制剂的设计、合成及抗三阴性乳腺癌活性研究  

Design,synthesis and biological evaluation of saccharin-based HDACs inhibitors for the treatment of triple-negative breast cancer

作　　者：李晓萌 权梦谣 刘昱辰 侯旭奔 韩雷强 方浩 LI Xiao-meng;QUAN Meng-yao;LIU Yu-chen;HOU Xu-ben;HAN Lei-qiang;FANG Hao(Department of Pharmacy,the Second Hospital of Shandong University,Ji'nan 250033,China;School of Pharmaceutical Science,Key Laboratory of Chemical Biology(Ministry of Education),Shandong University,Ji'nan 250012,China)

机构地区：[1]山东大学第二医院药学部,山东济南250033 [2]山东大学药学院,天然产物化学生物学教育部重点实验室,山东济南250012

出　　处：《药学学报》2024年第11期3017-3026,共10页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(81874288)。

摘　　要：作为一种关键的表观遗传调节因子,组蛋白去乙酰化酶(histone deacetylases,HDACs)在癌症的发展中发挥着重要作用。小分子HDACs抑制剂已被证明能够抑制肿瘤增殖并诱导细胞凋亡,因此受到了广泛的研究关注。本研究设计和合成了一系列新的邻苯甲酰磺酰亚胺衍生物作为HDACs抑制剂。生物学实验表明,目标化合物9a展现出优于vorinostat的HDACs抑制活性,且对三阴性乳腺癌(triple-negative breast cancer,TNBC)具有良好的体内外抗肿瘤活性。所有动物实验经山东大学药学院伦理委员会批准(批准号:230094)。该项工作是以邻苯甲酰磺酰亚胺为母核发展HDACs抑制剂的一次探索,以9a为代表的活性化合物可以作为先导化合物进一步研究。As a key epigenetic regulator,histone deacetylases(HDACs)play a crucial role in cancer development.Small molecule HDAC inhibitors have been shown to inhibit tumor proliferation and induce apoptosis,attracting significant research attention.In this study,we designed and synthesized a series of novel saccharin derivatives as HDAC inhibitors.Biological experiments demonstrated that the target compound 9a exhibited superior HDACs inhibition activity to vorinostat and demonstrating promising in vitro and in vivo antitumor activity against triple-negative breast cancer(TNBC).All animal experiments in this study were performed in strict accordance with the protocols approved by the Ethical Committee of School of Pharmaceutical Sciences in Shandong University(Approval No.230094).This work represents an initial exploration of developing saccharinbased HDAC inhibitors,and the active compound 9a could serve as a lead compound for further study.

关 键 词：邻苯甲酰磺酰亚胺 HDAC抑制剂 抗肿瘤 三阴性乳腺癌 构效关系 

分 类 号：R914[医药卫生—药物化学]