A long-linker conjugate of fluorescein and triphenylphosphonium as mitochondria-targeted uncoupler and fluorescent neuro- and nephroprotector

Mitochondrial membrane potential

“…Consequently, under specific cases of poorly regulated ΔΨm and ROS elevations “mild uncouplers” could potentially have beneficial properties in limiting the ravages of a number of diseases, including those associated with aging [73], obesity [74,75] and pathologies accompanied by oxidative stress, such as stroke and heart attack [76–78]. Therefore, an extensive search has been initiated among the compounds with various chemical structures for new drugs which could potentially be tested therapeutically as “mild uncouplers” of oxidative phosphorylation [79–84]. …”

Fluorescein Derivatives as Antibacterial Agents Acting via Membrane Depolarization

“…At present, there is a revival of interest in uncouplers because of the growing evidence of their broad-spectrum therapeutic efficacy [1][2][3][4][5][6][7][8][9], including antibacterial potency [10][11][12][13][14][15][16][17][18][19], which was actually found very early [20]. To this end, a series of esters of fluorescein were obtained and studied at our laboratory, manifesting themselves as rather effective mitochondrial uncouplers [21][22][23]. Amongst them, the most intriguing compound was fluorescein decyl(triphenyl)phosphonium ester (mitoFluo, Figure 1), which was able to accumulate in energized mitochondria due to a cationic triphenylphosphonium (TPP) moiety, which was readily monitored via its bright fluorescence [22], and which exhibited neuro-and nephroprotective properties [23].…”

“…To this end, a series of esters of fluorescein were obtained and studied at our laboratory, manifesting themselves as rather effective mitochondrial uncouplers [21][22][23]. Amongst them, the most intriguing compound was fluorescein decyl(triphenyl)phosphonium ester (mitoFluo, Figure 1), which was able to accumulate in energized mitochondria due to a cationic triphenylphosphonium (TPP) moiety, which was readily monitored via its bright fluorescence [22], and which exhibited neuro-and nephroprotective properties [23]. Our data revealed the necessity of a long alkyl linker between the cationic moiety and the proton-dissociating (fluorescein) fragment to render mitoFluo a mitochondria-targeted uncoupler [22,23].…”

“…Amongst them, the most intriguing compound was fluorescein decyl(triphenyl)phosphonium ester (mitoFluo, Figure 1), which was able to accumulate in energized mitochondria due to a cationic triphenylphosphonium (TPP) moiety, which was readily monitored via its bright fluorescence [22], and which exhibited neuro-and nephroprotective properties [23]. Our data revealed the necessity of a long alkyl linker between the cationic moiety and the proton-dissociating (fluorescein) fragment to render mitoFluo a mitochondria-targeted uncoupler [22,23]. To further improve the membrane permeability of mitoFluo, thereby enhancing its membrane potential-driven accumulation in mitochondria, in this study we synthesized fluorescein decyl(tri-p-tolyl)phosphonium ester (tol-mitoFluo, Figure 1).…”

Aged kidney: can we protect it? Autophagy, mitochondria and mechanisms of ischemic preconditioning

“…Thus, drug-induced uncoupling will decrease the drug accumulation, thereby forming a negative reverse link preventing energy collapse of mitochondria. Currently, the nephroprotective potential of two such new compounds, dodecylrhodamine (С12R1) [98] and mitoFluo [109], has been proven. In the nearest future, we can expect the emergence of new uncouplers with an increasingly wide therapeutic window.…”