Tuning NO release of organelle-targeted furoxan derivatives and their cytotoxicity against lung cancer cells

We herein report a study on a set of hybrid compounds in which 3-R-substituted furoxan moieties (R = CH3, CONH2, CN, SO2C6H5), endowed with varying NO-releasing capacities, are joined to a mitochondrial probe, rhodamine B. Each product has been investigated for its ability to release NO both in physiological solution, in the presence of cysteine, and in A549 lung adenocarcinoma cancer cells. The cytotoxicity of all the products against the aforementioned cancer cells has been assessed, including the structurally related compounds with no mitochondrial targeting, which were taken as a reference. In the case of the models bearing the -CH3 and -CONH2 groups at the 3-position on the furoxan, only the targeted models showed a significant cytotoxic activity, and only at the highest concentrations, in accordance with their weak NO-releasing properties. On the contrary, the presence of the strong electron-withdrawing groups, as -CN and -SO2C6H5, at the 3-position gave rise to anticancer agents, likely because of the high NO-releasing and of their capability of inhibiting cellular proteins by covalent binding. In detail, the rhodamine hybrid containing the 3-SO2C6H5 substituted furoxan moiety emerged as the most interesting product as it showed high cytotoxicity over the entire concentration range tested. This substructure was also linked to a phenothiazine scaffold that is able to accumulate in lysosomes. Nevertheless, mitochondrial targeting for these NO-donor furoxan substructures was found to be the most efficient.

Automated summary

This study investigated a set of hybrid compounds with different nitric oxide (NO) releasing capacities, composed of 3-R-substituted furoxan moieties linked to a mitochondrial probe, rhodamine B. Strong electron-withdrawing groups at the 3-position of the furoxan showed high cytotoxicity likely due to their high NO-releasing properties and ability to inhibit cellular proteins by covalent binding. The most interesting product was identified as the rhodamine hybrid containing 3-SO2C6H5 substituted furoxan moiety, showing high cytotoxicity over the entire concentration range tested.