Novel Sigma Receptor Ligand-Nitric Oxide Photodonors: Molecular Hybrids for Double-Targeted Antiproliferative Effect

This contribution reports the synthesis and evaluation of novel hybrid compounds that conjugate a sigma (sigma) receptor pharmacophore and a nitric oxide (NO) photodonor. All compounds preserve their capability to generate NO under visible light and possess overall sigma receptor nanomolar affinity, with one of them (8b) exhibiting remarkable sigma(2) receptor, selectivity. compounds 8b, 11a, and 11b were tested on tumorigenic MCF-7 and A2058 cells expressing high levels of sigma(2) and sigma(1) receptor, 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 nontumorigenic NCTC-2544 keratinocytes. NO-induced reduction of cellular viability was demonstrated by in-cell NO detection and total nitrite estimation. For the first time, combination of sigma receptor moieties and a NO photodonor is reported, providing distinctive ligands potentially useful for cancer management.