Highly malignant triple-negative breast cancer (TNBC) cells rely mostly on glycolysis to maintain cellular homeostasis; however, mitochondria are still required for migration and metastasis. Taking advantage of the metabolic flexibility of TNBC MDA-MB-231 cells to generate subpopulations with glycolytic or oxidative phenotypes, we screened phenolic compounds containing an ortho-carbonyl group with mitochondrial activity and identified a bromoalkyl-ester of hydroquinone named FR58P1a, as a mitochondrial metabolism-affecting compound that uncouples OXPHOS through a protonophoric mechanism. In contrast to well-known protonophore uncoupler FCCP, FR58P1a does not depolarize the plasma membrane and its effect on the mitochondrial membrane potential and bioenergetics is moderate suggesting a mild uncoupling of OXPHOS. FR58P1a activates AMPK in a Sirt1-dependent fashion. Although the activation of Sirt1/AMPK axis by FR58P1a has a cyto-protective role, selectively inhibits fibronectin-dependent adhesion and migration in TNBC cells but not in non-tumoral MCF10A cells by decreasing β1-integrin at the cell surface. Prolonged exposure to FR58P1a triggers a metabolic reprograming in TNBC cells characterized by down-regulation of OXPHOS-related genes that promote cell survival but comprise their ability to migrate. Taken together, our results show that TNBC cell migration is susceptible to mitochondrial alterations induced by small molecules as FR58P1a, which may have therapeutic implications.

Photoreduction of 5,6-dimethoxy-, 5-methoxy- and 2,3-dihydro-7H-dibenzo[de,h]quinolin-7-one (A) by tertiary amines in oxygen-free solutions generates long-lived semi-reduced metastable photoproducts, A-NH(-), via a stepwise electron-proton-electron transfer mechanism with a limit quantum yield of about 0.1 at high TEA concentrations. These metastable photoproducts revert thermally to the initial oxoisoaporphine nearly quantitatively in the presence or absence of oxygen. We present spectrophotometric, NMR and UV-vis data for the metastable photoproducts. The spectrophotometric results and PM3 and ZINDO/S calculations support the proposed mechanism for the photoreduction of the oxoisoaporphines.

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