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 (σ) receptor pharmacophore
and a nitric oxide (NO) photodonor. All compounds preserve their capability
to generate NO under visible light and possess overall σ receptor
nanomolar affinity, with one of them (8b) exhibiting
remarkable σ2 receptor selectivity. Compounds 8b, 11a, and 11b were tested on
tumorigenic MCF-7 and A2058 cells expressing high levels of σ2 and σ1 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, a combination of σ receptor
moieties and a NO photodonor is reported, providing distinctive ligands
potentially useful for cancer management.