Novel Sigma Receptors Ligands-Nitric Oxide Photodonor: Molecular Hybrids for Double-Targeted Antiproliferative Effect

This contribution reports the synthesis and evaluation of novel hybrid compounds that conjugate a sigma (σ) receptors pharmacophore and a nitric oxide (NO) photodonor. All compounds preserve their capability to generate NO under visible light and possess overall σ receptors nanomolar affinity, with one of them (8b) exhibiting remarkable σ2receptor selectivity. Compounds 8b, 11a, and 11b were tested on tumorigenic MCF-7 and A2058 cells expressing high levels of σ2and σ1receptor, respectively. Considerable loss of cell viability was detected under light excitation while negligible effects in the dark were detected. Moreover, they did not show any significant cytotoxicity in the dark or under irradiation on non-tumorigenic NCTC-2544 keratinocytes. NO-induced reduction of cellular viability was demonstrated by in cell NO detection and total nitrite estimation. For the first time, a combination of σ receptors moieties and a NO photodonor is reported, providing distinctive ligands potentially useful for cancer management.