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Synthesis and Pharmacological Evaluation of σ2 Receptor Ligands Based on a 3‐Alkoxyisoxazole Scaffold: Potential Antitumor Effects against Osteosarcoma
Author(s) -
Shi JunJie,
Jia KunHang,
Sun Hao,
Gunosewoyo Hendra,
Yang Fan,
Tang Jie,
Luo Jian,
Yu LiFang
Publication year - 2021
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000461
Subject(s) - hacat , osteosarcoma , chemistry , stereochemistry , receptor , cell culture , cytotoxicity , apoptosis , scaffold , cell growth , cancer research , pharmacology , biochemistry , biology , medicine , in vitro , genetics , biomedical engineering
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 [(2 S )‐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 K i value of 7.9 nM. It demonstrated potent antiproliferative effects on both osteosarcoma cell lines 143B and MOS−J (IC 50 values of 0.89 and 0.71 μM, respectively), relative to siramesine (IC 50 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.