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

We report the development of molecular hybrids in which a nitrate group serving as nitric oxide (NO) donor is covalently joined to sigma receptor ligands to give candidates for double-targeted cancer therapy. The compounds have been evaluated in radioligand binding assay at both sigma 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 sigma(1), receptor antagonist/sigma(2) 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 sigma receptors and the NO-mediated events. Overall, the combination of NO donor and sigma receptors ligands provided compounds with beneficial effects for the treatment of cancer.