Abstract
Mitochondria-targeting drugs and diagnostics are used in the monitoring and treatment of mitochondrial pathologies. In this respect, a great number of functional compounds have been made mitotropic by covalently attaching the active moiety onto a triphenylphosphonium (TPP) cation. Among these compounds, a number of molecular detectors for reactive oxygen species (ROS) are based on fluorescent and chemiluminescent probes. In this regard, luminol (probably the most widely known chemiluminescent molecule) has been employed for a number of biological applications, including ROS detection. Its oxidation under specific conditions triggers a cascade of reactions, ultimately leading to the excited 3-aminophthalate (3AP *), which emits light upon deactivation. Hence, the photophysical interaction between the light-emitting species 3AP * and TPP cations needs to be evaluated, as it can add valuable information on the design of novel emission-based mitotropic systems. We herein investigate the quenching effect of ethyltriphenylphosphonium cation onto substituted 3-aminophthalates. These were prepared in situ upon hydrolysis of the corresponding anhydrides, which were synthesized from 3-aminophthalimides. Steady-state fluorescence and time-resolved experiments were employed for the evaluation of a possible electron transfer quenching by phosphonium ions. Our experimental results confirmed such quenching, suggesting it is mainly dynamic in nature. A minor contribution of static quenching that was also detected is attributed to complex formation in the ground state. Accordingly, the chemiluminescence of luminol was indeed strongly reduced in the presence of phosphonium ions. Our results have to be taken into account during the design of new chemiluminescent mitotropic drugs or diagnostic agents of the luminol family.
Highlights
Mitochondria are acknowledged as the subcellular organelles directly affecting both life, as cell’s energy powerhouses, and death, as apoptosis regulators [1–3]
The course of the reactions was monitored with thin-layer chromatography (TLC), using aluminum sheets (0.2 mm) coated with silica gel 60 with fluorescence indicator
A series of 3-aminophthalates (1a–c) have been prepared in situ via alkaline hydrolysis of the corresponding 3-aminophthalic acid anhydrides. The latter are the hydrolysis products of the analogous substituted 3-aminophthalimides, which derive from N-alkylation and/or Suzuki methylation of the parent phthalimide. 3-Aminophthalates’ fluorescence is strongly quenched by ethyltriphenylphosphonium cation, with dynamic rate constants in the order of 109 M−1s−1, close to the diffusion limit
Summary
Mitochondria are acknowledged as the subcellular organelles directly affecting both life, as cell’s energy powerhouses, and death, as apoptosis regulators [1–3]. Rendering drugs and diagnostics mitotropic (or mitochondriotropic), that is, achieving organelle-specific accumulation, is a way for monitoring and treating mitochondrial pathologies. Triphenylphosphonium cations (TPPCs) stand out, both due to their exceptional mitotropic activity and ease of synthesis. RiteosutrltospanicdsDyissctuesmsiso.nTo the best of our knowledge, the photophysical evalua as aWmeihnaovpe chhtohseanlatoteinqvuesetingacthe ethresqiusenpcrheinsgeneftfeecdt ohf ethreeefthoyrlttrhipehefniryslpthtoismpheo.nium (ETPP) cation onto phthalates 1a–c and 3AP (Figure 2). The p rpeshutlhteadliantethse1foar–mcatwioansofatchceormesppelcitsivheeadnhaysdrfiodlelso6wa–sc:, i3n-satemadinofotphehctohrarelsimpoinddeing[2] was b pinhtghaelixccaecisdss,binrdoimcatiinnge ainninascietutiicntaracmidoletcouwlaar rcodnsdepnhsatthioanl.imThiedseea3nh(yFdirgiduersew3er)e This w ftthoiueoynndwateloirzeheyuddserodvlyaiaszetahineSibruainszicsuiatkuqiup–erMoeucuisyrmsaoeurdsria(asteocewoFuaigrpduslrietnhSge1ciwonrtriheteshpSotunrpdipminlegemtpehhnytthalarblyaotMresoa1txeair–nicae,lss)ot.o give dimethyl phthalimide 4. 6a–c, instead of the corresponding phthalic acids, indicating an in situ intram densation. These anhydrides were found to hydrolyze in basic aqueous m the corresponding phthalates 1a–c, so they were used as their in situ precu ure S1 in the Supplementary Materials). Τhe marked weakening of phthalate fluorescence upon 3-amino alkylation
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