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

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.

Recent Advances in the Development of Sigma Receptor Ligands as Cytotoxic Agents: A Medicinal Chemistry Perspective

“…Very recently, small molecules characterized by the presence of the 3-alkoxyisoxazole moiety have been designed and evaluated for their potential binding properties toward the σRs. 176 This chemical scaffold was identified from the superimposition of the pharmacophoric elements required for a righteous binding to both σ 1 and α4β2 nicotinic receptors. 177 Compound 82 ( Figure 30 ) was detected as a σ 1 R ligand with high affinity and selectivity over the σ 2 R subtype.…”

Synthesis and Biological Evaluation of Substituted 3‐Isoxazolethioethers as Antileishmanial and Antibacterial Agents

“…Isoxazole heterocycle [1] is tagged as a privileged motif owing to its representation in a variety of pharmacologically active compounds displaying bioactivities such as allosteric RORγt inverse agonist, [2] antimalarial, [3] antileishmanial, [4] σ2 receptor ligand, [5] EGFR‐TK inhibitor for cancer, [6] FLT3 inhibitors for acute myeloid leukemia [7] and antiviral agents [8] . Additionally, isoxazole derivatives form part of several agrochemicals, [9] advanced organic materials, [10] and serve as intermediates in organic synthesis for preparing chemically useful compounds [11] .…”