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

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.

Keywords: Anticancer activity; Homopiperazine; Indanone; Oxime; Sigma receptors; Sigma-2 receptor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology
  • Azepines / chemistry*
  • Azepines / metabolism
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cisplatin / pharmacology
  • Drug Screening Assays, Antitumor
  • Haloperidol / analogs & derivatives*
  • Haloperidol / chemistry
  • Haloperidol / metabolism
  • Humans
  • Ligands
  • Receptors, sigma / chemistry
  • Receptors, sigma / metabolism*
  • Structure-Activity Relationship

Substances

  • 4-(4-(4-chlorophenyl)-1,4-diazepan-1-yl)-1-(4-fluorophenyl)butan-1-one
  • Antineoplastic Agents
  • Azepines
  • Ligands
  • Receptors, sigma
  • sigma-2 receptor
  • Haloperidol
  • Cisplatin