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

Emanuele Amata; Maria Dichiara; Davide Gentile; Agostino Marrazzo; Rita Turnaturi; Emanuela Arena; Alfonsina La Mantia; Barbara Rita Tomasello; Rosaria Acquaviva; Claudia Di Giacomo; Antonio Rescifina; Orazio Prezzavento

doi:10.1021/acsmedchemlett.9b00661

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. eCollection 2020 May 14.

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.

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.