title: Discovery of 2-methoxy-3-phenylsulfonamino-5-(quinazolin-6-yl or quinolin-6-yl)benzamides as novel PI3K inhibitors and anticancer agents by bioisostere.
abstract: 2-Substituted-3-sulfonamino-5-(quinazolin-6-yl or quinolin-6-yl)benzamides have been proposed as novel structures of PI3K inhibitors and anticancer agents based on bioisostere. In the present study, 2-substituted-3-sulfonamino-5-(4-morpholinoquinazolin-6-yl)benzamides and 2-methoxy-3-sulfonamino-5-(4-morpholinoquinolin-6-yl)benzamides were synthesized. Their antiproliferative activities in vitro were evaluated via MTT assay against four human cancer cell lines, including A549, HCT-116, U-87 MG and KB. The SAR of the title compounds was preliminarily discussed. Compound 1a with potent antiproliferative activity was tested for its inhibitory activity against PI3K and mTOR and its effect on the AKT and p-AKT(473). The anticancer effect of 1a was evaluated in established nude mice U-87 MG xenograft model. The results suggest that compound 1a can significantly inhibit PI3K/AKT/mTOR pathway and tumor growth. These findings strongly support the assumption that title compounds are potent PI3K inhibitors and anticancer agents.
authors: Department of Medicinal Chemistry, School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, PR China.
authors: Teng
authors: T
authors: Shao
authors: Center for Pharmacological Evaluation and Research, Shanghai Institute of Pharmaceutical Industry, Shanghai 200437, PR China.
authors: Juan
authors: J
authors: Wang
authors: Department of Medicinal Chemistry, School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, PR China.
authors: Jian-Gang
authors: JG
authors: Chen
authors: Department of Medicinal Chemistry, School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, PR China.
authors: Xiao-Meng
authors: XM
authors: Wang
authors: Department of Medicinal Chemistry, School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, PR China.
authors: Huan
authors: H
authors: Li
authors: Department of Medicinal Chemistry, School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, PR China.
authors: Yi-Ping
authors: YP
authors: Li
authors: Department of Medicinal Chemistry, School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, PR China.
authors: Yan
authors: Y
authors: Li
authors: Department of Medicinal Chemistry, School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, PR China.
authors: Guang-De
authors: GD
authors: Yang
authors: Center for Pharmacological Evaluation and Research, Shanghai Institute of Pharmaceutical Industry, Shanghai 200437, PR China. Electronic address: qbmei@hotmail.com.
authors: Qi-Bing
authors: QB
authors: Mei
authors: Department of Medicinal Chemistry, School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, PR China. Electronic address: sqzhang@xjtu.edu.cn.
authors: San-Qi
authors: SQ
authors: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D001549:Benzamides / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011799:Quinazolines; D058570:TOR Serine-Threonine Kinases
keywords: Anticancer effect; Antiproliferative activity; Benzamide; Bioisostere; PI3K inhibitor; Quinazoline