title: Preparation of S14161 and its analogues and the discovery of 6-bromo-8-ethoxy-3-nitro-2H-chromene as a more potent antitumor agent in vitro.
abstract: The small chemical compound 8-ethoxy-2-(4-fluorophenyl)-3-nitro-2H-chromene (S14161) was recently identified as an inhibitor of the phosphoinositide 3-kinase (PI3K). In the present study, we designed a novel synthesis of S14161 and prepared a series of its analogues via the oxa-Michael-Henry reaction in the presence of catalytic amounts of l-proline and triethylamine. Further structural simplification led to the identification of 6-bromo-8-ethoxy-3-nitro-2H-chromene (BENC-511) that exhibited potent antiproliferative activities against a panel of 12 tumor cell lines. Compared with S14161, BENC-511 was more potent in blocking the AKT phosphorylation and inducing cancer cell apoptosis. BENC-511 also displayed more potent effects on human umbilical vein epithelial cells (HUVEC) migration, suggesting its anti-angiogenesis activity.
authors.affiliation: Department of Organic Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong Province, PR China.
authors.forename: Shu-Qiang
authors.initials: SQ
authors.lastname: Yin
authors.forename: Min
authors.initials: M
authors.lastname: Shi
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Kong
authors.forename: Cheng-Mei
authors.initials: CM
authors.lastname: Zhang
authors.forename: Kunkun
authors.initials: K
authors.lastname: Han
authors.forename: Biyin
authors.initials: B
authors.lastname: Cao
authors.forename: Zubin
authors.initials: Z
authors.lastname: Zhang
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Du
authors.forename: Long-Qian
authors.initials: LQ
authors.lastname: Tang
authors.forename: Xinliang
authors.initials: X
authors.lastname: Mao
authors.forename: Zhao-Peng
authors.initials: ZP
authors.lastname: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D002384:Catalysis; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004354:Drug Screening Assays, Antitumor; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D062105:Molecular Docking Simulation; D018919:Neovascularization, Physiologic / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000737:chemistry; D011392:Proline / Q000737:chemistry; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001578:Benzopyrans; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines; D011392:Proline; D051057:Proto-Oncogene Proteins c-akt; C584755:6-bromo-8-ethoxy-3-nitro-2H-chromene; C557120:8-ethoxy-2-(4-fluorophenyl)-3-nitro-2H-chromene; C007306:triethylenediamine