title: Synthesis and evaluation of novel benzylphthalazine derivatives as hedgehog signaling pathway inhibitors.
abstract: We report herein the design and synthesis of a series of novel benzylphthalazine derivatives as hedgehog signaling pathway inhibitors. Gli-luciferase assay demonstrated that changing piperazine ring of Anta XV to different four, five or six-membered heterocyclic building blocks afforded significant influences on Hh pathway inhibition. In particular, compound 10e with piperidin-4-amine moiety was found to possess 12-fold higher Hh inhibitory activities comparing to the lead compound in vitro. In vivo efficacy of 10e in a ptch(+/-)p53(-/-) mouse medulloblastoma allograft model also indicated encouraging results.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, PR China.
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Bao
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, PR China.
authors.forename: Yuanqiu
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, PR China.
authors.forename: Xiuhong
authors.initials: X
authors.lastname: Lu
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, PR China. Electronic address: zhaoweili@fudan.edu.cn.
authors.forename: Weili
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, PR China. Electronic address: wftan@fudan.edu.cn.
authors.forename: Wenfu
authors.initials: W
authors.lastname: Tan
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, PR China. Electronic address: xcdong@fudan.edu.cn.
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Dong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D053823:Hedgehog Proteins / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D010793:Phthalazines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013329:Structure-Activity Relationship
chemical_list: C000621106:2-(6-((1-(4-benzylphthalazin-1-yl)piperidin-4-yl)amino)pyridin-3-yl)propan-2-ol; C000621105:Anta XV; D000970:Antineoplastic Agents; D053823:Hedgehog Proteins; D010793:Phthalazines; D010879:Piperazines
keywords: Anti-tumor agents; Benzylphthalazines; Hedgehog signaling pathway; Inhibitors