Synthesis and Pharmacological Evaluation of σ2 Receptor Ligands Based on a 3-Alkoxyisoxazole Scaffold: Potential Antitumor Effects against Osteosarcoma |
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| Authors: | Jun-Jie Shi Dr Kun-Hang Jia Dr Hao Sun Dr Hendra Gunosewoyo Prof Fan Yang Prof Jie Tang Prof Jian Luo Prof Li-Fang Yu |
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| Affiliation: | 1. Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062 China;2. Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai, 200241 China
These authors contributed equally to this work.;3. School of Pharmacy and Biomedical Sciences Faculty of Health Sciences, Curtin University, Bentley, Perth, WA, 6102 Australia;4. Shanghai Key Laboratory of Green Chemistry and Chemical Process School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062 China;5. Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai, 200241 China |
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| Abstract: | Since its initial discovery as the basis for nicotinic acetylcholine receptor ligands, the 3-alkoxyisoxazole scaffold has been shown to be a versatile platform for the development of potent σ1 and σ2 receptor ligands. Herein we report a further SAR exploration of the 3-alkoxyisoxazole scaffold with the aim of obtaining potent σ2 receptor ligands. Various substitutions on the benzene ring and at the basic amino regions resulted in a total of 21 compounds that were tested for their binding affinities for the σ2 receptor. In particular, compound 51 (2S)-1-(4-ammoniobutyl)-2-(((5-((3,4-dichlorophenoxy)methyl)isoxazol-3-yl)oxy)methyl)pyrrolidin-1-ium chloride] was identified as one of the most potent σ2 ligands within the series, with a Ki value of 7.9 nM. It demonstrated potent antiproliferative effects on both osteosarcoma cell lines 143B and MOS?J (IC50 values of 0.89 and 0.71 μM, respectively), relative to siramesine (IC50 values of 1.81 and 2.01 μM). Moreover, compound 51 inhibited clonal formation of osteosarcoma 143B cells at 1 μM, corresponding to half the dose required of siramesine for similar effects. The general cytotoxicity profile of compound 51 was assessed in a number of normal cell lines, including HaCaT, HAF, and LO2 cells. Furthermore, FACS analysis showed that compound 51 likely inhibits osteosarcoma cell growth by disruption of the cell cycle and promotion of apoptosis. |
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| Keywords: | σ2 receptor 3-alkoxyisoxazoles osteosarcoma antiproliferative effects colony formation cytotoxicity siramesine |
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