Details

Autor(en) / Beteiligte

• Shi, Jun‐Jie
• Jia, Kun‐Hang
• Sun, Hao
• Gunosewoyo, Hendra
• Yang, Fan
• Tang, Jie
• Luo, Jian
• Yu, Li‐Fang

Titel

Synthesis and Pharmacological Evaluation of σ2 Receptor Ligands Based on a 3‐Alkoxyisoxazole Scaffold: Potential Antitumor Effects against Osteosarcoma

Ist Teil von

• ChemMedChem, 2021-02, Vol.16 (3), p.524-536

Ort / Verlag

Germany: Wiley Subscription Services, Inc

Erscheinungsjahr

2021

Link zum Volltext

Quelle

Wiley Online Library

Beschreibungen/Notizen

• 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. A further SAR exploration of the 3‐alkoxyisoxazole scaffold with the aim of obtaining potent σ2 receptor ligands is reported. Halogen substitution on the benzene ring and introduction of an alkylamino group at the basic N atom resulted in compound 51 as one of the most potent σ2 ligands, showing potent antiproliferative effects on two osteosarcoma cell lines. Compound 51 also has lower cytotoxicity toward normal cells, and was demonstrated to inhibit clone formation, induce cell‐cycle arrest and apoptosis of osteosarcoma cells.