Sigma Receptor Ligands Carrying a Nitric Oxide Donor Nitrate Moiety: Synthesis, In Silico, and Biological Evaluation

  • ACS Med Chem Lett. 2020 Apr 9;11(5):889-894. doi: 10.1021/acsmedchemlett.9b00661.
Emanuele Amata  1 ,  Maria Dichiara  1 ,  Davide Gentile  2 ,  Agostino Marrazzo  1 ,  Rita Turnaturi  1 ,  Emanuela Arena  1 ,  Alfonsina La Mantia  3 ,  Barbara Rita Tomasello  3 ,  Rosaria Acquaviva  3 ,  Claudia Di Giacomo  3 ,  Antonio Rescifina  2 ,  Orazio Prezzavento  1
Affiliations
  • 1. Department of Drug Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria, 95125 Catania, Italy.
  • 2. Department of Drug Sciences, Chemistry Section, University of Catania, Viale A. Doria, 95125 Catania, Italy.
  • 3. Department of Drug Sciences, Biochemistry Section, University of Catania, Viale A. Doria, 95125 Catania, Italy.
PMID: 32435401 DOI: 10.1021/acsmedchemlett.9b00661
Abstract

We report the development of molecular hybrids in which a nitrate group serving as nitric oxide (NO) donor is covalently joined to σ receptor ligands to give candidates for double-targeted Cancer therapy. The compounds have been evaluated in radioligand binding assay at both σ receptors and selected compounds tested for NO release. Compounds 9, 15, 18, 19, and 21 were subjected to MTT test. Compound 15 produced a significant reduction of MCF-7 and Caco-2 cellular viability with comparable IC50 as doxorubicin, being also not toxic for fibroblast HFF-1 cells. Compound 15 has shown a σ1 receptor antagonist/σ2 receptor agonist profile. Two derivatives of compound 15 lacking the nitrate group did not induce a reduction of MCF-7 cellular viability, suggesting a potential synergistic effect between the σ receptors and the NO-mediated events. Overall, the combination of NO donor and σ receptors ligands provided compounds with beneficial effects for the treatment of Cancer.