Structure-activity relationships study of neolamellarin A and its analogues as hypoxia inducible factor-1 (HIF-1) inhibitors |
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| Authors: | Guangzhe Li Huijuan Dong Yao Ma Kun Shao Yueqing Li Xiaodan Wu Shisheng Wang Yujie Shao Weijie Zhao |
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| Institution: | 1. Department of Pharmacy, School of Chemical Engineering, Dalian University of Technology, Dalian 116023, China;2. State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116023, China;3. Dalian Hospital of Obstetrics and Gynaecology, Dalian 116083, China |
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| Abstract: | The novel marine pyrrole alkaloid neolamellarin A derived from sponge has been shown to inhibit hypoxia-induced HIF-1 activity. In this work, we designed and synthesized neolamellarin A and its series of derivatives by a convergent synthetic strategy. The HIF-1 inhibitory activity and cytotoxicity of these compounds were evaluated in Hela cells by dual-luciferase reporter gene assay and MTT assay, respectively. The results showed that neolamellarin A 1 (IC50 = 10.8 ± 1.0 μM) and derivative 2b (IC50 = 11.9 ± 3.6 μM) had the best HIF-1 inhibitory activity and low cytotoxicity. Our SAR research focused on the effects of key regions aliphatic carbon chain length, aromatic ring substituents and C-7 substituent on biological activity, providing a basis for the subsequent research on the development of novel pyrrole alkaloids as HIF-1 inhibitors and design of small molecule probes for target protein identification. |
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| Keywords: | Corresponding author at: Department of Pharmacy School of Chemical Engineering Dalian University of Technology Dalian 116023 China Anti-tumor Hypoxia inducible factor (HIF)-1 Marine alkaloids Neolamellarin A Structure-activity relationship |
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