Design, Synthesis and Molecular Docking Analysis of Flavonoid Derivatives as Potential Telomerase Inhibitors
Zhan-Fang Fan,
Sai-Tim Ho,
Rui Wen,
Ya Fu,
Lei Zhang,
Jian Wang,
Chun Hu,
Pang-Chui Shaw,
Yang Liu,
Mao-Sheng Cheng
Affiliations
Zhan-Fang Fan
Key Laboratory of Structure-Based Drugs Design and Discovery (Ministry of Education), School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
Sai-Tim Ho
School of Life Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, China
Rui Wen
Key Laboratory of Structure-Based Drugs Design and Discovery (Ministry of Education), School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
Ya Fu
Key Laboratory of Structure-Based Drugs Design and Discovery (Ministry of Education), School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
Lei Zhang
Key Laboratory of Structure-Based Drugs Design and Discovery (Ministry of Education), School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
Jian Wang
Key Laboratory of Structure-Based Drugs Design and Discovery (Ministry of Education), School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
Chun Hu
Key Laboratory of Structure-Based Drugs Design and Discovery (Ministry of Education), School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
Pang-Chui Shaw
School of Life Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, China
Yang Liu
Key Laboratory of Structure-Based Drugs Design and Discovery (Ministry of Education), School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
Mao-Sheng Cheng
Key Laboratory of Structure-Based Drugs Design and Discovery (Ministry of Education), School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
Based on the structural scaffolds of natural products, two series of flavonoid derivatives, for a total of twelve compounds, were designed and synthesized as potential human telomerase inhibitors. Using a modified TRAP-PCR assay, compound 5c exhibited the most potent inhibitory activity against human telomerase with an IC50 value of less than 50 μM. In vitro, the results demonstrated that compound 5c had potent anticancer activity against five classes of tumor cell lines. The molecular docking and molecular dynamics analyses binding to the human telomerase holoenzyme were performed to elucidate the binding mode of active compound 5c. This finding helps the rational design of more potent telomerase inhibitors based on the structural scaffolds of natural products.
