新型 SYA013 类似物作为具有抗癌活性的 sigma-2 配体。
New analogs of SYA013 as sigma-2 ligands with anticancer activity.
机构信息
Division of Basic Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.
出版信息
Bioorg Med Chem. 2019 Jun 15;27(12):2629-2636. doi: 10.1016/j.bmc.2019.04.012. Epub 2019 Apr 8.
Abstract
Our previous study has revealed 4-(4-(4-chlorophenyl)-1,4-diazepan-1-yl)-1-(4-fluorophenyl)butan-1-one·2HCl (SYA013) 1 as a sigma ligand with moderate selectivity for the sigma-2 receptor. Given the overexpression of sigma receptors in solid tumors and reports of sigma ligands with anticancer activities, we selected 1 for evaluation in several solid tumor cell lines. In addition, we have synthesized new analogs of 1 and now report that several of them bind preferentially at the sigma-2 receptor and have shown inhibition of several cancer cell lines including MDA-MB-231, MDA-MB-486, A549, PC-3, MIA PaCa-2 and Panc-1 cells. In particular, compounds 1 and 12 have demonstrated sub-micromolar activity against the Panc-1 cell line. It has also been observed that several of these compounds demonstrate selective toxicity toward cancer cells, when compared to normal cells.
摘要
我们之前的研究揭示了 4-(4-(4-氯苯基)-1,4-二氮杂环庚烷-1-基)-1-(4-氟苯基)丁-1-酮·2HCl（SYA013）1 是一种 sigma 配体，对 sigma-2 受体具有中等选择性。鉴于 sigma 受体在实体瘤中的过度表达以及具有抗癌活性的 sigma 配体的报道，我们选择 1 用于评估几种实体瘤细胞系。此外，我们已经合成了 1 的新类似物，现在报告说其中一些优先与 sigma-2 受体结合，并已显示抑制包括 MDA-MB-231、MDA-MB-486、A549、PC-3、MIA PaCa-2 和 Panc-1 细胞在内的几种癌细胞系。特别是，化合物 1 和 12 对 Panc-1 细胞系表现出亚微摩尔活性。还观察到，与正常细胞相比，这些化合物中的一些对癌细胞表现出选择性毒性。
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