title: Combination of 2-methoxy-3-phenylsulfonylaminobenzamide and 2-aminobenzothiazole to discover novel anticancer agents.
abstract: The fragment of 2-substituted-3-sulfonylaminobenzamide has been proposed to replace the fragment of 2-substituted-3-sulfonylaminopyridine in PI3K and mTOR dual inhibitors to design novel anticancer agents based on bioisostere. The combination of the fragment of 2-substituted-3-sulfonylaminobenzamide with the fragment of 2-aminobenzothiazole or 2-aminothiazolo[5,4-b]pyridine, or 2-amino[1,2,4]triazolo[1,5-a]pyridine produced the novel structures of anticancer agents. As a result, nineteen target compounds were synthesized and characterized. Their antiproliferative activities in vitro were evaluated via MTT assay against four human cancer cell lines including HCT-116, A549, MCF-7 and U-87 MG. The SAR of target compounds was preliminarily discussed. Compound 1g with potent antiproliferative activity was examined for its effect on the AKT and p-AKT(473). The anticancer effect of 1g was evaluated in established nude mice HCT-116 xenograft model. The results suggested that compound 1g can block PI3K/AKT/mTOR pathway and significantly inhibit tumor growth. These findings strongly support our assumption that the fragment of benzamide can replace the pyridine ring in some PI3K and mTOR dual inhibitor to design novel anticancer agents.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, PR China.
authors.forename: Huan
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, PR China.
authors.forename: Xiao-Meng
authors.initials: XM
authors.lastname: Wang
authors.affiliation: Center for Pharmacological Evaluation and Research, Shanghai Institute of Pharmaceutical Industry, Shanghai 200437, PR China.
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, PR China.
authors.forename: Teng
authors.initials: T
authors.lastname: Shao
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, PR China.
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Li
authors.affiliation: Center for Pharmacological Evaluation and Research, Shanghai Institute of Pharmaceutical Industry, Shanghai 200437, PR China.
authors.forename: Qi-Bing
authors.initials: QB
authors.lastname: Mei
authors.affiliation: Department of Genetics and Molecular Biology, School of Medicine, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, PR China.
authors.forename: She-Min
authors.initials: SM
authors.lastname: Lu
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, PR China. Electronic address: sqzhang@mail.xjtu.edu.cn.
authors.forename: San-Qi
authors.initials: SQ
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D052160:Benzothiazoles / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D045325:HCT116 Cells; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: C000593982:5-(2-acetamidobenzo(d)thiazol-6-yl)-3-(4-fluorophenylsulfonylamino)-2-methoxybenzamide; D000970:Antineoplastic Agents; D052160:Benzothiazoles; D013449:Sulfonamides
keywords: Anticancer effect; Benzamide; Benzothiazole; Bioisostere; Synthesis