title: Modification of N-(6-(2-methoxy-3-(4-fluorophenylsulfonamido)pyridin-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)acetamide as PI3Ks inhibitor by replacement of the acetamide group with alkylurea.
abstract: N-(6-(2-Methoxy-3-(4-fluorophenylsulfonamido)pyridin-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)acetamide exhibits remarkable anticancer effects and toxicity when orally administrated. In present study, alkylurea moiety replaced the acetamide group in the compound and a series of 1-alkyl-3-(6-(2-methoxy-3-sulfonylaminopyridin-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)urea derivatives were synthesized. The antiproliferative activities of the synthesized compounds in vitro were evaluated against four human cancer cell lines. Several compounds with potent antiproliferative activities were tested for their acute oral toxicity and their inhibitory activity against PI3Ks and mTOR. The results indicate that the compound attached a alkylurea or 2-(dialkylamino)ethylurea moiety at the 2-position of [1,2,4]triazolo[1,5-a]pyridine can retain the antiproliferative activity and the inhibitory activity against PI3Ks and mTOR. In addition, their acute oral toxicity reduced dramatically. Moreover, the results also indicate that compound 1e can efficaciously inhibit tumor growth in a mice S180 model. These findings suggest that title compounds can serve as potent PI3K inhibitors and effective anticancer agents with low toxicity.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China.
authors.forename: Xiao-Meng
authors.initials: XM
authors.lastname: Wang
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Mao
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China.
authors.forename: Lei
authors.initials: L
authors.lastname: Cao
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China.
authors.forename: Xiao-Xiao
authors.initials: XX
authors.lastname: Xie
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China.
authors.forename: Min-Hang
authors.initials: MH
authors.lastname: Xin
authors.affiliation: Medical Technology Department, Bethune Medical NCO School of PLA, Shijiazhuang, Hebei 050081, PR China.
authors.forename: Jia-Fang
authors.initials: JF
authors.lastname: Lian
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China.
authors.forename: Yong-Xiao
authors.initials: YX
authors.lastname: Cao
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China. Electronic address: sqzhang@xjtu.edu.cn.
authors.forename: San-Qi
authors.initials: SQ
authors.lastname: Zhang
mesh_terms: D000081:Acetamides; D000818:Animals; D049109:Cell Proliferation; D055808:Drug Discovery; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry*
chemical_list: D000081:Acetamides; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014508:Urea; C030686:acetamide
keywords: Acute toxicity; Anticancer agent; PI3K inhibitors; Urea; [1,2,4]Triazolo[1,5-a]pyridine