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.
Highlights
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 σ1 receptor has been identified as a ligand-operated chaperone protein localized in the mitochondria-associated endoplasmic reticulum (ER) membranes (MAM)
At the MAM, the σ1 receptor forms a complex with another chaperone, the immunoglobulin heavy-chain binding protein (BiP)
Summary
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 synthesized compounds were evaluated for affinity at both σ1 and σ2 receptors through radioligand binding assay (Table 1). 16), the meta-substituted compound 9 has shown a preferential σ1 receptor affinity with Ki value of 49 nM, and 330 nM for the σ2 receptor.
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