title: Design, synthesis and biological evaluation of N-phenylquinazolin-4-amine hybrids as dual inhibitors of VEGFR-2 and HDAC.
abstract: A single agent that simultaneously inhibits multiple targets may offer greater therapeutic benefits in cancer than single-acting agents through interference with multiple pathways and potential synergistic action. In this work, a series of hybrids bearing N-phenylquinazolin-4-amine and hydroxamic acid moieties were designed and identified as dual VEGFR-2/HDAC inhibitors. Compound 6fd exhibited the most potent inhibitory activity against HDAC with IC50 of 2.2 nM and strong inhibitory effect against VEGFR-2 with IC50 of 74 nM. It also showed the most potent inhibitory activity against a human breast cancer cell line MCF-7 with IC50 of 0.85 μM. Docking simulation supported the initial pharmacophoric hypothesis and suggested a common mode of interaction at the active binding sites of VEGFR-2 and HDLP ((Histone Deacetylase-Like Protein), which demonstrates that compound 6fd is a potential agent for cancer therapy deserving further researching.
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, PR China.
authors.forename: Fan-Wei
authors.initials: FW
authors.lastname: Peng
authors.affiliation: 81 Hospital of PLA, Nanjing, 210002, PR China.
authors.forename: Ji
authors.initials: J
authors.lastname: Xuan
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, PR China.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Wu
authors.affiliation: Jiangsu Provincial Key Laboratory for Plant Ex Situ Conservation, Institute of Botany, Jiangsu Province and Chinese Academy of Sciences, Nanjing, 210014, PR China.
authors.forename: Jia-Yu
authors.initials: JY
authors.lastname: Xue
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, PR China.
authors.forename: Zi-Wei
authors.initials: ZW
authors.lastname: Ren
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, PR China.
authors.forename: Da-Ke
authors.initials: DK
authors.lastname: Liu
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, PR China.
authors.forename: Xiu-Qi
authors.initials: XQ
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, PR China.
authors.forename: Xin-Hang
authors.initials: XH
authors.lastname: Chen
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, PR China.
authors.forename: Jia-Wei
authors.initials: JW
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, PR China. Electronic address: xyg@cpu.edu.cn.
authors.forename: Yun-Gen
authors.initials: YG
authors.lastname: Xu
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, PR China. Electronic address: shilei@cpu.edu.cn.
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
mesh_terms: D000586:Amination; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D062105:Molecular Docking Simulation; D011799:Quinazolines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D056572:Histone Deacetylase Inhibitors; D011799:Quinazolines; D040301:Vascular Endothelial Growth Factor Receptor-2; D006655:Histone Deacetylases
keywords: Dual inhibitor; HDAC; N-Phenylquinazolin-4-amine hybrid; VEGFR-2