New analogs of SYA013 as sigma-2 ligands with anticancer activity

• Published in: Bioorganic & medicinal chemistry Vol. 27; no. 12; pp. 2629 - 2636
• Main Authors: Asong, Gladys, Zhu, Xue Y., Bricker, Barbara, Andey, Terrick, Amissah, Felix, Lamango, Nazarius, Ablordeppey, Seth Y.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.06.2019; Elsevier
• Subjects: Anticancer activity; Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Azepines - chemistry; Azepines - metabolism; Biochemistry & Molecular Biology; Cell Line, Tumor; Cell Survival - drug effects; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Cisplatin - pharmacology; Drug Screening Assays, Antitumor; Haloperidol - analogs & derivatives; Haloperidol - chemistry; Haloperidol - metabolism; Homopiperazine; Humans; Indanone; Life Sciences & Biomedicine; Ligands; Oxime; Pharmacology & Pharmacy; Physical Sciences; Receptors, sigma - chemistry; Receptors, sigma - metabolism; Science & Technology; Sigma receptors; Sigma-2 receptor; Structure-Activity Relationship; Indanone; Oxime; Sigma receptors; Sigma-2 receptor; Homopiperazine; Anticancer activity; PROLIFERATION; IDENTIFICATION; MICHAEL ADDITION; BREAST-CANCER; GENE; CLONING; RECEPTORS; BINDING; EXPRESSION
• ISSN: 0968-0896; 1464-3391; 1464-3391
• DOI: 10.1016/j.bmc.2019.04.012

[Display omitted] 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.