title: Synthesis and biological evaluation of N-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)benzenesulfonamide derivatives as new BET bromodomain inhibitors for anti-hematologic malignancies activities.
abstract: The bromodomain and extra-terminal proteins (BETs), in particular BRD4, has been reported to play important roles in cancer, inflammation, obesity, cardiovascular disease, and neurological disorders. In this paper, a series of benzomorpholinone derivatives were synthesized and biologically evaluated as BETs inhibitors. Detailed structure-activity relationship studies led to the discovery of several new potent compounds, of which 15h and 15i displayed [Formula: see text] values of 2.8 and 4.5 [Formula: see text] against BRD4 (D1), respectively, and showed good anti-proliferation activities against four hematologic malignancies cell lines at low-micromolar concentrations, including MV4-11, OCI-LY10, Pfeifer, and Su-DHL-6 cells. This chemotype could be further optimized with respect to its potency and drug-like properties in the future.
authors.affiliation: Department of Pharmaceutical and Bioengineering, School of Chemical Engineering, Sichuan University, # 24, Section 1, Ren Min Nan Lu, Chengdu, 610000, China.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, # 17, Section 3, Ren Min Nan Lu, Chengdu, 610041, China.
authors.forename: Yongxia
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, # 17, Section 3, Ren Min Nan Lu, Chengdu, 610041, China.
authors.forename: Zhihao
authors.initials: Z
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, # 17, Section 3, Ren Min Nan Lu, Chengdu, 610041, China.
authors.forename: Tinghong
authors.initials: T
authors.lastname: Ye
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, # 17, Section 3, Ren Min Nan Lu, Chengdu, 610041, China.
authors.forename: Weiqiong
authors.initials: W
authors.lastname: Zuo
authors.affiliation: Department of Pharmaceutical and Bioengineering, School of Chemical Engineering, Sichuan University, # 24, Section 1, Ren Min Nan Lu, Chengdu, 610000, China.
authors.forename: Cuiting
authors.initials: C
authors.lastname: Peng
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, # 17, Section 3, Ren Min Nan Lu, Chengdu, 610041, China.
authors.forename: Kunjie
authors.initials: K
authors.lastname: Xiao
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, # 17, Section 3, Ren Min Nan Lu, Chengdu, 610041, China. scuwny059@163.com.
authors.forename: Ningyu
authors.initials: N
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutical and Bioengineering, School of Chemical Engineering, Sichuan University, # 24, Section 1, Ren Min Nan Lu, Chengdu, 610000, China. yuluot@scu.edu.cn.
authors.forename: Luoting
authors.initials: L
authors.lastname: Yu
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic; D019337:Hematologic Neoplasms / Q000473:pathology*; D006801:Humans; D000072417:Protein Domains; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000096926:Benzenesulfonamides
chemical_list: D000970:Antineoplastic Agents; D013449:Sulfonamides; D000096926:Benzenesulfonamides
keywords: Anti-proliferation activity; BET inhibitor; BRD4; Benzomorpholinone; Structure–activity relationship