title: Synthesis and anticancer effects evaluation of 1-alkyl-3-(6-(2-methoxy-3-sulfonylaminopyridin-5-yl)benzo[d]thiazol-2-yl)urea as anticancer agents with low toxicity.
abstract: As a PI3K and mTOR dual inhibitor, N-(2-chloro-5-(2-acetylaminobenzo[d]thiazol-6-yl)pyridin-3-yl)-4-fluorophenylsulfonamide displays toxicity when orally administrated. In the present study, alkylurea moiety replaced the acetamide group in the compound and a series of 1-alkyl-3-(6-(2,3-disubstituted pyridin-5-yl)benzo[d]thiazol-2-yl)urea derivatives were synthesized. The antiproliferative activities of the synthesized compounds in vitro were evaluated against HCT116, MCF-7, U87 MG and A549 cell lines. The compounds with potent antiproliferative activity were tested for their acute oral toxicity and inhibitory activity against PI3Ks and mTORC1. The results indicate that the compound attached a 2-(dialkylamino)ethylurea moiety at the 2-positeion of benzothiazole can retain the antiproliferative activity and inhibitory activity against PI3K and mTOR. In addition, their acute oral toxicity reduced dramatically. Moreover, compound 2f can effectively inhibit tumor growth in a mice S180 homograft model. These findings suggest that 1-(2-dialkylaminoethyl)-3-(6-(2-methoxy-3-sulfonylaminopyridin-5-yl)benzo[d]thiazol-2-yl)urea derivatives can serve as potent PI3K inhibitors and anticancer agents with low toxicity.
authors: Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China.
authors: Xiao-Xiao
authors: XX
authors: Xie
authors: Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China.
authors: Huan
authors: H
authors: Li
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, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China.
authors: Shuai
authors: S
authors: Mao
authors: Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China.
authors: Min-Hang
authors: MH
authors: Xin
authors: Department of Genetics and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China.
authors: She-Min
authors: SM
authors: Lu
authors: Center for Pharmacological Evaluation and Research, Shanghai Institute of Pharmaceutical Industry, Shanghai 200437, PR China.
authors: Qi-Bing
authors: QB
authors: Mei
authors: Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China. Electronic address: sqzhang@xjtu.edu.cn.
authors: San-Qi
authors: SQ
authors: Zhang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D052160:Benzothiazoles / Q000737:chemistry; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D045325:HCT116 Cells; D006801:Humans; D061986:MCF-7 Cells; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D062105:Molecular Docking Simulation; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D014184:Transplantation, Homologous; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D052160:Benzothiazoles; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D058570:TOR Serine-Threonine Kinases; D014508:Urea; C005465:benzothiazole
keywords: Acute toxicity; Anticancer; Benzo[d]thiazole; PI3K inhibitor; Urea