Design, synthesis and biological evaluation of N-phenylquinazolin-4-amine hybrids as dual inhibitors of VEGFR-2 and HDAC
- Eur J Med Chem. 2016 Feb 15:109:1-12. doi: 10.1016/j.ejmech.2015.12.033.
- 1. Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, PR China.
- 2. 81 Hospital of PLA, Nanjing, 210002, PR China.
- 3. Jiangsu Provincial Key Laboratory for Plant Ex Situ Conservation, Institute of Botany, Jiangsu Province and Chinese Academy of Sciences, Nanjing, 210014, PR China.
- 4. Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, PR China. Electronic address: [email protected].
- 5. Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, PR China. Electronic address: [email protected].
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.