title: Five-membered heteroaromatic ring fused-pyrimidine derivatives: design, synthesis, and hedgehog signaling pathway inhibition study.
abstract: A series of novel five-membered heteroaromatic ring fused-pyrimidine derivatives including purines, pyrrolo[2,3-d]pyrimidines, pyrrolo[3,2-d]pyrimidines, thieno[2,3-d]pyrimidines, thieno[3,2-d]pyrimidines and furo[3,2-d]pyrimidines have been identified to be potent inhibitors of hedgehog signaling pathway. The synthesis and SAR of these compounds are described. Among this new series of hedgehog signaling pathway inhibitors, most compounds exhibited significant inhibitory activity compared to vismodegib, indicating that the five-membered heteroaromatic ring fused-pyrimidines stand out as encouraging scaffolds among the currently reported structural skeletons for hedgehog signaling pathway inhibitors, deserving more exploration and further investigation.
authors.affiliation: The College of Biotechnology and Pharmaceutical Engineering, Nanjing University of Technology, No. 30 Puzhu Road, Nanjing 211800, PR China; Jiangsu Simcere Pharmaceutical Co. Ltd, Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No. 699-18, Xuan Wu District, Nanjing 210042, PR China.
authors.forename: Liandi
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an 710061, PR China. Electronic address: xmhcpu@163.com.
authors.forename: Minhang
authors.initials: M
authors.lastname: Xin
authors.affiliation: Jiangsu Simcere Pharmaceutical Co. Ltd, Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No. 699-18, Xuan Wu District, Nanjing 210042, PR China.
authors.forename: Han
authors.initials: H
authors.lastname: Shen
authors.affiliation: Jiangsu Simcere Pharmaceutical Co. Ltd, Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No. 699-18, Xuan Wu District, Nanjing 210042, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wen
authors.affiliation: Jiangsu Simcere Pharmaceutical Co. Ltd, Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No. 699-18, Xuan Wu District, Nanjing 210042, PR China.
authors.forename: Feng
authors.initials: F
authors.lastname: Tang
authors.affiliation: Jiangsu Simcere Pharmaceutical Co. Ltd, Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No. 699-18, Xuan Wu District, Nanjing 210042, PR China.
authors.forename: Chongxing
authors.initials: C
authors.lastname: Tu
authors.affiliation: Jiangsu Simcere Pharmaceutical Co. Ltd, Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No. 699-18, Xuan Wu District, Nanjing 210042, PR China.
authors.forename: Xinge
authors.initials: X
authors.lastname: Zhao
authors.affiliation: The College of Biotechnology and Pharmaceutical Engineering, Nanjing University of Technology, No. 30 Puzhu Road, Nanjing 211800, PR China. Electronic address: weiping@njtech.edu.cn.
authors.forename: Ping
authors.initials: P
authors.lastname: Wei
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D053823:Hedgehog Proteins; D006576:Heterocyclic Compounds, 4 or More Rings; D011743:Pyrimidines; C030986:pyrimidine
keywords: Five-membered heteroaromatic ring fused-pyrimidine; Hedgehog signaling pathway; Inhibitors; Synthesis