Department of Chemical and Pharmaceutical Sciences, University of Trieste, Via Giorgieri 1, 34127 Trieste, Italy.
Department of Life Sciences, University of Trieste, Via Valerio 28, 34127 Trieste, Italy.
Molecules. 2024 Jun 6;29(11):2697. doi: 10.3390/molecules29112697.
Sigma receptors (SRs), including SR1 and SR2 subtypes, have attracted increasing interest in recent years due to their involvement in a wide range of activities, including the modulation of opioid analgesia, neuroprotection, and potential anticancer activity. In this context, haloperidol (HAL), a commonly used antipsychotic drug, also possesses SR activity and cytotoxic effects. Herein, we describe the identification of novel SR ligands, obtained by a chemical hybridization approach. There wereendowed with pan-affinity for both SR subtypes and evaluated their potential anticancer activity against SH-SY5Y and HUH-7 cancer cell lines. Through a chemical hybridization approach, we identified novel compounds (, , , and ) with dual affinity for SR1 and SR2 receptors. These compounds were subjected to cytotoxicity testing using a resazurin assay. The results revealed potent cytotoxic effects against both cancer cell lines, with IC values comparable to HAL. Interestingly, the cytotoxic potency of the novel compounds resembled that of the SR1 antagonist HAL rather than the SR2 agonist siramesine (SRM), indicating the potential role of SR1 antagonism in their mechanism of action. The further exploration of their structure-activity relationships and their evaluation in additional cancer cell lines will elucidate their therapeutic potential and may pave the way for the development of novel anticancer agents that target SRs.
近年来，由于 sigma 受体（SRs）参与了广泛的活动，包括阿片类药物镇痛的调节、神经保护和潜在的抗癌活性，因此受到了越来越多的关注。其中，氟哌啶醇（HAL）作为一种常用的抗精神病药物，也具有 SR 活性和细胞毒性作用。在此，我们通过化学杂交方法鉴定了新型 SR 配体。这些配体对 SR1 和 SR2 亚型均具有泛亲和力，并评估了它们对 SH-SY5Y 和 HUH-7 癌细胞系的潜在抗癌活性。通过化学杂交方法，我们鉴定了对 SR1 和 SR2 受体具有双重亲和力的新型化合物（、、、和）。这些化合物通过 Resazurin 测定法进行了细胞毒性测试。结果表明，这些化合物对两种癌细胞系均具有很强的细胞毒性作用，IC 值与 HAL 相当。有趣的是，新型化合物的细胞毒性效价类似于 SR1 拮抗剂 HAL，而不类似于 SR2 激动剂 siramesine（SRM），这表明 SR1 拮抗作用可能是其作用机制的一部分。进一步探索它们的构效关系，并在其他癌细胞系中评估它们，将阐明它们的治疗潜力，并可能为开发靶向 SRs 的新型抗癌药物铺平道路。
