Triphenylphosphonium Cation Research Articles

First Report on Cationic Triphenylphosphonium Compounds as Mitochondriotropic H3R Ligands with Antioxidant Properties.

Neurodegenerative diseases are a major public health problem due to the aging population and multifaceted pathology; therefore, the search for new therapeutic alternatives is of the utmost importance. In this sense, a series of six 1-(3-phenoxypropyl)piperidines alkyl-linked to a triphenylphosphonium cation derivative were synthesized as H3R ligands with antioxidant properties to regulate excessive mitochondrial oxidative stress and contribute to potential new therapeutic approaches for neurodegenerative diseases. Radioligand displacement studies revealed high affinity for H3R with Ki values in the low to moderate two-digit nanomolar range for all compounds. Compound 6e showed the highest affinity (Ki H3R = 14.1 nM), comparable to that of pitolisant. Antioxidative effects were evaluated as radical-scavenging properties using the ORAC assay, in which all derivatives showed low to moderate activity. On the other hand, cytotoxic effects in SH-SY5Y neuroblastoma cells were investigated using the colorimetric alamar blue assay, which revealed significant effects on cell viability with an unequivocally structure-toxicity relationship. Finally, docking and molecular simulation studies were used to determine the H3R binding form, which will allow us to further modify the compounds to establish a robust structure-activity relationship and find a lead compound with therapeutic utility in neurodegenerative diseases.

Detouring NSAID into Mitochondria to Induce Apoptosis in Cancer Cells.

In recent years, impairing mitochondria in cancer cells gained attention as alternative cancer therapy. In this context, non-steroidal anti-inflammatory (NSAID) drugs are interesting candidates to damage mitochondria in cancer cells. However, routing NSAIDs specifically into the mitochondria remained a major challenge and less explored. Herein, we have synthesized a small library of Meclofenamic acid and Naproxen derivatives having ester and amide linkage with substituted triphenylphosphonium cations for mitochondria targeting. Screening in cervical cancer (HeLa), breast cancer (MCF7) and colon cancer (HCT-116) cells revealed a Meclofenamic acid derivative having ester linkage with tri (4-methoxyphenyl) phosphonium cation (8A3) which induced mitochondrial damage through mitochondrial outer membrane permeabilization (MOMP) followed by generation of reactive oxygen species (ROS) in the HCT-116 cells. This 8A3-mediated mitochondrial impairment triggered apoptosis by inhibiting Cox-2, reduction in Bcl-2/Bcl-xl expression and Caspase-3/9 cleavage leading to remarkable HCT-116 cell death. This novel mitochondrion targeted Meclofenamic acid derivative has the potential to be used as a chemical biology tool to understand the role of NSAIDs in mitochondria towards cancer therapy.

Rod‐Like Microcrystal Scintillators Based on Organic–Inorganic Hybrid Copper Halides for X‐Ray Imaging

AbstractCopper‐based organic–inorganic hybrid halides (OIHHs) have garnered significant interest in X‐ray imaging due to their flexible structural adjustability, efficient light emission, strong X‐ray absorption, etc. Herein, four copper‐based OIHH crystals composed of the same organic ligands (isopropyl triphenylphosphonium cations, IPP+) and inorganic parts (Cu2I42−) are synthesized by varying the ratios of raw materials and types of reaction solvents. Although these crystals share identical structures, they exhibit different luminescent behaviors (blue, green, white, and yellow) attributed to vacancy defects originating from CuI. Notably, the novel copper‐based OIHH (CP2) with green emission shows the best luminescence efficiency (99.54%) and excellent scintillation performance (50675 photons MeV−1). The traditional technology of scintillation screens mixing scintillator powders and polymers often results in light scattering due to powder aggregation and inhomogeneity. To address this challenge, the dispersant polyvinyl pyrrolidone is introduced to prepare uniform rod‐like microcrystals of CP2. The scintillation screen based on CP2 microcrystals achieves a high spatial resolution of 16–18 lp mm−1, surpassing the resolution of most copper‐based OIHH scintillators. Furthermore, it is imaging capabilities are validated using a commercial X‐ray flat panel detector, demonstrating imaging performance comparable to that of commercial scintillators.

Copper(II) and Zinc(II) complexes of new water-soluble Schiff base ligands and their antiproliferative properties towards mesothelioma cell line

In this work, three Schiff base ligands (HL1-HL3) containing a triphenyl phosphonium cation and their Cu(II) and Zn(II) complexes with the general formulae of [M(L)Cl2] were synthesized and their structures were characterized by spectroscopic and analytical methods. Crystal structure of complex [Zn(L1)Cl2] was determined. In the structure of the complex, each Zn(II) ion is four coordinated binding to phenolate oxygen and imine nitrogen atoms of the ligand L1 and two chloride atoms in approximately tetrahedral geometry. The equilibrium geometry of three Schiff base ligands (HL1-HL3) and their Cu(II) and Zn(II) complexes were calculated using the density functional theory (DFT/B3LYP) method with the 6–31++G(d,p) basis set for the C, H, Cl, N, O, P atoms and LANL2DZ for the I atom. Frontier molecular orbitals (HOMO, LUMO) analyses were conducted for the optimized geometries of the compounds, and chemical reactivity descriptors such as hardness, softness, electrophilicity, and electronegativity were examined. Additionally, the molecular electrostatic potential (MEP) of all compounds was modeled using DFT calculations. These calculations were thoroughly examined, and their implications were discussed. The ligands and their metal complexes were investigated for their DNA binding properties. The compounds showed comparable DNA binding properties to ethidium bromide (EB) and 5-fluorouracyl (5-Fu) with DNA binding constant (Kb) 1.5–6.25 × 105 M−1. The cytotoxic properties of the compounds towards HUVEC and H2452 (mesothelioma cell line) cells were investigated using an MTS assay. The IC50 values determined for HUVEC cells were found to range between 27.28 µg/mL ([Cu(L2)Cl2]) and 273.1 µg/mL ([Zn(L2)Cl2]), while in H2452 cells, they varied from 39.48 µg/mL ([Cu(L2)Cl2]) to 319.3 µg/mL ([Zn(L3)Cl2]). The compounds HL1, HL3, and [Zn(L3)Cl2] exhibited antioxidant activity at the highest concentration (750 µg/mL) only, while [Zn(L1)Cl2], HL2, [Zn(L2)Cl2], [Cu(L2)Cl2], and [Cu(L3)Cl2] showed antioxidant activity at 250 µg/mL.

Puerarin-Loaded Liposomes Co-Modified by Ischemic Myocardium-Targeting Peptide and Triphenylphosphonium Cations Ameliorate Myocardial Ischemia-Reperfusion Injury.

Mitochondrial damage may lead to uncontrolled oxidative stress and massive apoptosis, and thus plays a pivotal role in the pathological processes of myocardial ischemia-reperfusion (I/R) injury. However, it is difficult for the drugs such as puerarin (PUE) to reach the mitochondrial lesion due to lack of targeting ability, which seriously affects the expected efficacy of drug therapy for myocardial I/R injury. We prepared triphenylphosphonium (TPP) cations and ischemic myocardium-targeting peptide (IMTP) co-modified puerarin-loaded liposomes (PUE@T/I-L), which effectively deliver the drug to mitochondria and improve the effectiveness of PUE in reducing myocardial I/R injury. In vitro test results showed that PUE@T/I-L had sustained release and excellent hemocompatibility. Fluorescence test results showed that TPP cations and IMTP double-modified liposomes (T/I-L) enhanced the intracellular uptake, escaped lysosomal capture and promoted drug targeting into the mitochondria. Notably, PUE@T/I-L inhibited the opening of the mitochondrial permeability transition pore, reduced intracellular reactive oxygen species (ROS) levels and increased superoxide dismutase (SOD) levels, thereby decreasing the percentage of Hoechst-positive cells and improving the survival of hypoxia-reoxygenated (H/R)-injured H9c2 cells. In a mouse myocardial I/R injury model, PUE@T/I-L showed a significant myocardial protective effect against myocardial I/R injury by protecting mitochondrial integrity, reducing myocardial apoptosis and decreasing infarct size. This drug delivery system exhibited excellent mitochondrial targeting and reduction of myocardial apoptosis, which endowed it with good potential extension value in the precise treatment of myocardial I/R injury.

Synthesis and comparative analysis of the cytotoxicity and mitochondrial effects of triphenylphosphonium and F16 maslinic and corosolic acid hybrid derivatives

The cytotoxic profile and antiproliferative and mitochondrial effects of triterpene acid conjugates with mitochondriotropic lipophilic triphenylphosphonium (TPP+) and F16 cations were evaluated. Maslinic and corosolic acids chosen as the investigation objects were synthesized from commercially available oleanolic and ursolic acids. Study of the cytotoxic activity of TPP+ and F16 triterpenoid derivatives against six tumor cell lines demonstrated a comparable synergistic effect in the anticancer activity, which was most pronounced in the case of MCF-7 mammary adenocarcinoma cells and Jurkat and THP-1 leukemia cells. The corosolic and maslinic acid hybrid derivatives caused changes in the progression of tumor cell cycle phases when present in much lower doses than their natural triterpene acid precursors. The treatment of tumor cell lines with the conjugates resulted in the cell cycle arrest in the G1 phase and increase in the cell population in the subG1 phase. The cationic derivatives of the acids were markedly superior to their precursors as inducers of hyperproduction of reactive oxygen species and more effectively decreased the mitochondrial potential in isolated rat liver mitochondria. We concluded that the observed cytotoxic effect of TPP+ and F16 triterpenoid conjugates is attributable to the ability of these compounds to initiate mitochondrial dysfunctions. Their cytotoxicity, antiproliferative action, and mitochondrial effects depend little on the type of cationic groups used.

Phytopathogenic Fungicidal Activity and Mechanism Approach of Three Kinds of Triphenylphosphonium Salts.

The triphenylphosphonium (TPP) cation has been widely used as a carrier for mitochondria-targeting molecules. We synthesized two commonly employed targeting systems, namely, ω-triphenylphosphonium fatty acids (group 2) and ω-triphenylphosphonium fatty alcohols (group 3), to assess the impact of the TPP module on the biological efficacy of mitochondria-targeting molecules. We evaluated their fungicidal activities against nine plant pathogenic fungi in comparison to alkyl-1-triphenylphosphonium compounds (group 1). All three compound groups exhibited fungicidal activity and displayed a distinct "cut-off effect", which depended on the length of the carbon chain. Specifically, group 1 compounds showed a cut-off point at C10 (compound 1-7), while group 2 and 3 compounds exhibited cut-off points at C15 (compound 2-12) and C14 (compound 3-11), respectively. Notably, group 1 compounds displayed significantly higher fungicidal activity compared to groups 2 and 3. However, group 2 and 3 compounds showed similar activity to each other, although susceptibility may depend on the pathogen tested. Initial investigations into the mechanism of action of the most active compounds suggested that their fungicidal performance may be primarily attributed to their ability to damage the membrane, as well as uncoupling activity and inhibition of fungal respiration. Our findings suggest that the TPP module used in delivery systems as aliphatic acyl or alkoxyl derivatives with carbon chains length < 10 will contribute negligible fungicidal activity to the TPP-conjugate compared to the effect of high level of accumulation in mitochondria due to its mitochondria-targeting ability. These results provide a foundation for utilizing TPP as a promising carrier in the design and development of more effective mitochondria-targeting drugs or pesticides.

Ultraviolet up-conversion luminescent tetrahalozincates(II) with triphenylphosphonium cation: Synthesis, optical properties, and DFT calculations

Luminescent [HL]2[ZnX4] [X = Cl, Br] tetrahalozincate(II) compounds with triphenylphosphonium cation (HL = Ph3PH) were isolated using hydrohalic acids. This study reports the synthesis, crystal structures, and photophysical properties of novel tetrahalozincate(II) compounds. The [HL]2[ZnCl4] and [HL]2[ZnBr4] crystallize in the P21/c monoclinic and Pbca rhombic space groups, respectively. The compounds exhibit a strong ultraviolet (UV–B, λmax ≈ 290 nm) fluorescence and blue-green and green phosphorescence in solid state, with a high quantum efficiency (up to 78 %). The luminescence mechanism was investigated, revealing that the UV-B and green emissions are ascribed to the {ZnX4}h-{Ph3PH}e exciton-phonon emission, and the blue-green emission arises from the transition within the organic moiety. The [HL]2[ZnCl4] compound shows an unexpected up-conversion luminescence at 305 nm under 405 nm excitation, presumably caused by stepwise two-photon absorption accompanied by proton-coupled electron transfer. The up-conversion luminescence make this compounds a promising candidate for simple and cost-effective materials for visible-to-ultraviolet converter devices.

Self-assembly and functional activity of amphiphilic conjugates of the diterpenoid isosteviol and triphenylphosphonium cation, with focusing on biotechnological potential

Supramolecular systems based on amphiphilic triphenylphosphonium (TPP) conjugates of the diterpenoid isosteviol in which the diterpenoid skeleton and the TPP cation are linked by a polymethylene linker of varying length (n = 3, 6 or 8) have been fabricated. Elongation of this linker from 3 to 8 methylene units, allows for an 8-fold decrease in the amphiphile aggregation thresholds in aqueous solutions. These systems exhibit tunable self-assembly behavior, with the formation of both small aggregates (with a hydrodynamic diameter of ∼5–10 nm), as well as large vesicle-like structures (with a diameter of ∼50–100 nm), depending on the amphiphile concentration and length of the spacer fragment. The biotechnological potential of these amphiphiles has been demonstrated on the example of its membranotropic properties toward liposomes consisting of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC). Significant capacity for integration into lipid bilayer has been revealed in these amphiphiles, which could be increased by extending the length of the polymethylene linker. Cationic liposome formulations have been prepared on the basis of these amphiphiles and DPPC by a noncovalent modification approach. Sustainability of its DH and zeta potential during longtime storage has been demonstrated. The studied systems exhibit a selective cytotoxic effect on M-HeLa cancer cell line and are a less toxic to normal Chang liver cells. The mechanism of the cytotoxic action of the liposomes is associated with the induction of apoptosis through mitochondrial pathway. The obtained formulations have successfully been applied for metronidazole encapsulation, characterized by high encapsulation efficiency and loading capacity, as well as prolonged time of drug release.

Linking triphenylphosphonium cation to a bicyclic hydroquinone improves their antiplatelet effect via the regulation of mitochondrial function

Platelets are the critical target for preventing and treating pathological thrombus formation. However, despite current antiplatelet therapy, cardiovascular mortality remains high, and cardiovascular events continue in prescribed patients. In this study, first results were obtained with ortho-carbonyl hydroquinones as antiplatelet agents; we found that linking triphenylphosphonium cation to a bicyclic ortho-carbonyl hydroquinone moiety by a short alkyl chain significantly improved their antiplatelet effect by affecting the mitochondrial functioning. The mechanism of action involves uncoupling OXPHOS, which leads to an increase in mitochondrial ROS production and a decrease in the mitochondrial membrane potential and OCR. This alteration disrupts the energy production by mitochondrial function necessary for the platelet activation process. These effects are responsive to the complete structure of the compounds and not to isolated parts of the compounds tested. The results obtained in this research can be used as the basis for developing new antiplatelet agents that target mitochondria.

Probing the Use of Triphenyl Phosphonium Cation for Mitochondrial Nucleoside Delivery.

Herein, we report the design, the synthesis, and the study of novel triphenyl phosphonium-based nucleoside conjugates. 2'-Deoxycytidine was chosen as nucleosidic cargo, as it allows the introduction of fluorescein on the exocyclic amine of the nucleobase and grafting of the vector was envisaged through the formation of a biolabile ester bond with the hydroxyl function at the 5'-position. Compound 3 was identified as a potential nucleoside prodrug, showing ability to be internalized efficiently into cells and to be co-localized with mitochondria.

Synthesis, DNA binding and anticancer properties of new Cu(II) and Zn(II) complexes of a Schiff base ligand containing a triphenylphosphonium as a lipophilic cation

A new quinoline-Schiff base ligand (LTPP) containing the lipophilic triphenylphosphonium cation and its complexes [Cu(LTPP)Cl]Cl and [Zn(LTPP)Cl]Cl were synthesized and characterized. The structures of the ligand and metal complexes were characterized by FTIR, elemental analysis, NMR (for ligand), UV–Vis absorption and fluorescence spectroscopies. DNA binding interactions of the ligand and its metal complexes were investigated by UV–vis absorption and fluorescence spectroscopies as well as viscosity measurements. The DNA binding affinity (Kb) for the ligand and complexes [Cu(LTPP)Cl]Cl and [Zn(LTPP)Cl]Cl) obtained from absorption spectra were found as 4.33, 4.66 and 6.01 (×105 M−1), respectively. The ligand and its Cu(II) complex showed similar propensities to interact with DNA, yet the DNA binding affinity of the Zn(II) complex was relatively higher than free ligand and its Cu(II) complex. Docking studies were conducted in order to further investigate the DNA binding interactions. The ligand and its complexes were screened for their cytotoxic properties towards malignant mesothelioma (H2452) and healthy human umbilical vein endothelial (HUVEC) cells. The Cu(II) and Zn(II) complexes that were loaded into the cells (H2452) confirm their intracellular uptake by fluorescence-based cell imaging. Complex [Zn(LTPP)Cl]Cl emitted fluorescent light even after entering the cell suggesting that the compound can be used for cell tracking purposes. In order to find out whether the compounds we synthesized had the potency to enter human cells, we measured the florescent light emission of H2452 cells treated with the products at their IC50 concentration for 24 h. In vitro antioxidant properties of the ligand and its metal complexes were also studied.

Mitochondria dysfunction induced by decyl-TPP mitochondriotropic antioxidant based on caffeic acid AntiOxCIN6 sensitizes cisplatin lung anticancer therapy due to a remodeling of energy metabolism

The pharmacological interest in mitochondria is very relevant since these crucial organelles are involved in the pathogenesis of multiple diseases, such as cancer. In order to modulate cellular redox/oxidative balance and enhance mitochondrial function, numerous polyphenolic derivatives targeting mitochondria have been developed. Still, due to the drug resistance emergence in several cancer therapies, significant efforts are being made to develop drugs that combine the induction of mitochondrial metabolic reprogramming with the ability to generate reactive oxygen species, taking into consideration the varying metabolic profiles of different cell types. We previously developed a mitochondria-targeted antioxidant (AntiOxCIN6) by linking caffeic acid to lipophilic triphenylphosphonium cation through a 10-carbon aliphatic chain. The antioxidant activity of AntiOxCIN6 has been documented but how the mitochondriotropic compound impact energy metabolism of both normal and cancer cells remains unknown. We demonstrated that AntiOxCIN6 increased antioxidant defense system in HepG2 cells, although ROS clearance was ineffective. Consequently, AntiOxCIN6 significantly decreased mitochondrial function and morphology, culminating in a decreased capacity in complex I-driven ATP production without affecting cell viability. These alterations were accompanied by an increase in glycolytic fluxes. Additionally, we demonstrate that AntiOxCIN6 sensitized A549 adenocarcinoma cells for CIS-induced apoptotic cell death, while AntiOxCIN6 appears to cause metabolic changes or a redox pre-conditioning on lung MRC-5 fibroblasts, conferring protection against cisplatin. We propose that length and hydrophobicity of the C10-TPP+ alkyl linker play a significant role in inducing mitochondrial and cellular toxicity, while the presence of the antioxidant caffeic acid appears to be responsible for activating cytoprotective pathways.

Mitochondria-Targeting Multimodal Phototheranostics Based on Triphenylphosphonium Cation Modified Amphiphilic Pillararenes and A-D-A Fused-Ring Photosensitizers.

Tumor-targeting phototheranostics has gradually developed as a powerful tool for the precise diagnosis and treatment of cancer. However, the designs of tumor-targeting phototheranostics agents with excellent multimodal phototherapy and fluorescence imaging (FLI) capability, as well as very few components, are still scarce and challenging for cancer treatment. Herein, a mitochondria-targeting multimodal phototheranostics system has been constructed by combining a designed amphiphilic pillararene WP5-2PEG-2TPP and the A-D-A fused-ring photosensitizer F8CA5. WP5-2PEG-2TPP is constructed by attaching the triphenylphosphonium cations to our previously reported dual PEG-functionalized amphiphilic pillararene, which can self-assemble into regular spherical nanocarriers with outstanding mitochondria targeting and water solubility. The A-D-A photosensitizer F8CA5 containing two methyl cyanoacetate group modified end groups displays superior photothermal conversion ability and dual type I/II photodynamic activity as well as strong NIR fluorescence emission. Through their strong union, multifunctional mitochondria-targeting phototheranostics agent F8CA5 NPs were obtained to be applied into FLI-guided synergistic photothermal and type I/II photodynamic therapy. As a result, F8CA5 NPs show good mitochondria-targeting and phototherapy effects in various tumor cells. Not only that, they can combat tumor hypoxia, which hinders the efficacy of photodynamic therapy. Therefore, this work provides a creative ideal for the construction of multifunctional tumor-targeting phototheranostic agents with excellent performance.

Mitochondria-targeted melatonin photorelease supports the presence of melatonin MT1 receptors in mitochondria inhibiting respiration

The presence of signaling-competent G protein-coupled receptors in intracellular compartments is increasingly recognized. Recently, the presence of Gi/o protein-coupled melatonin MT1 receptors in mitochondria has been revealed, in addition to the plasma membrane. Melatonin is highly cell permeant, activating plasma membrane and mitochondrial receptors equally. Here, we present MCS-1145, a melatonin derivative bearing a triphenylphosphonium cation for specific mitochondrial targeting and a photocleavable o-nitrobenzyl group releasing melatonin upon illumination. MCS-1145 displayed low affinity for MT1 and MT2 but spontaneously accumulated in mitochondria, where it was resistant to washout. Uncaged MCS-1145 and exogenous melatonin recruited β-arrestin 2 to MT1 in mitochondria and inhibited oxygen consumption in mitochondria isolated from HEK293 cells only when expressing MT1 and from mouse cerebellum of WT mice but not from MT1-knockout mice. Overall, we developed the first mitochondria-targeted photoactivatable melatonin ligand and demonstrate that melatonin inhibits mitochondrial respiration through mitochondrial MT1 receptors.

Assessing mitochondria-targeted acyl hydroquinones on the mitochondrial platelet function and cytotoxic activity: Role of the linker length

IntroductionThe use of triphenylphosphonium cation (TPP+) linked to phenolic compounds by alkyl chains has a significant relevance as a mitochondrial delivery strategy in biomedicine because it affects mitochondrial bioenergetics in models of noncommunicable diseases such as cancer and cardiovascular-related conditions. Studies indicate that a long alkyl chain (10–12 carbon) increases the mitochondrial accumulation of TPP+-linked drugs. In contrast, other studies show that these compounds are consistently toxic to micromolar concentrations (as observed in platelets). In the present study, we evaluated the in vitro effect of three series of triphenylphosphonium-linked acyl hydroquinones derivates on the metabolism and function of human platelets using 3–9 carbons for the alkyl linker. Those were assessed to determine the role of the length of the alkyl chain linker on platelet toxicity. MethodsHuman platelets were exposed in vitro to different concentrations (2–40 μM) of every compound; cellular viability, phosphatidylserine exposition, mitochondrial membrane potential (ΔΨm), intracellular calcium release, and intracellular ROS generation were assessed by flow cytometry. An in silico energetic profile was generated with Umbrella sampling molecular dynamics (MD). Results and conclusionsThere was an increase in cytotoxic activity directly related to the length of the acyl chain and lipophilicity, as seen by three techniques, and this was consistent with a decrease in ΔΨm. The in silico energetic profiles point out that the permeability of the mitochondrial membrane may be involved in the cytotoxicity of phosphonium salts. This information may be relevant for the design of new TPP+ -based drugs with a safe cardiovascular profile.

New phosphorylated 5-(hydroxyalkylamino)-1,3-oxazoles as potential anticancer agents

Eight new phosphorylated 5-(hydroxyalkylamino)-1,3-oxazoles were designed and tested for their ability to inhibit cancer cell growth. These compounds were evaluated against complete human tumor cell lines NCI-60. Only three compounds showed antitumor activity in the single dose assay, which were taken in the five dose assay. Compounds 7 and 8 showed the same average antiproliferative activity and cytotoxicity against sensitive cell lines of the general panel. However, compound 8 showed cytotoxicity to more lines than 7. By all parameters, these compounds were more active than compounds 5. Compounds 7 and 8 also showed high and similar antiproliferative activity in the concentration range GI50: 1-6 and TGI: 6-14 μM against all subpanels. Their cytotoxicity was in the concentration range of 25-54 μM. Compound 5 showed the same activity, with the exception of the leukemia, non-small cell lung cancer and ovarian cancer subpanels against which their activity was lower. When analyzing the structure-activity, it turned out that among the phosphorylated oxazole derivatives, only compounds containing the triphenylphosphonium cation (TPP+) in the 4th position of the oxazole ring exhibit antitumor activity. Moreover, the replacement of the phenyl radical in the 2nd position of the oxazole scaffold with a methyl radical led to the disappearance of the activity. The COMPARE algorithm reveals a high correlation of the antiproliferative activity of the tested compounds with the antitumor agents phyllantoside and chromomycin A3 in the GI50 vector and moderate with phyllantoside in the TGI vector. The target of all standard drugs that correlate with the cytotoxicity of the studied compounds, with the exception of didemnin, is DNA. Unlike standard compounds, synthesized active compounds carry a delocalized TPP+, which delivers them predominantly to mitochondria due to a much more hyperpolarized potential of the mitochondrial membrane in cancer cells than in normal ones. Therefore, their anticancer activity is most likely due to a disturbation of the structural and functional state of the latter due to interference with their intrinsic protein-synthesizing apparatus of mitochondria. The data obtained allow us to consider 5-(hydroxyalkylamino)-1,3-oxazoles loaded with TPP+ as leading compounds for further in-depth study and synthesis of new TPP+-containing 1,3-oxazole derivatives with antitumor activity

Incorporating a Polyethyleneglycol Linker to Enhance the Hydrophilicity of Mitochondria-Targeted Triphenylphosphonium Constructs.

The targeting of bioactive molecules and probes to mitochondria can be achieved by coupling to the lipophilic triphenyl phosphonium (TPP) cation, which accumulates several hundred-fold within mitochondria in response to the mitochondrial membrane potential (Δψm ). Typically, a simple alkane links the TPP to its "cargo", increasing overall hydrophobicity. As it would be beneficial to enhance the water solubility of mitochondria-targeted compounds we explored the effects of replacing the alkyl linker with a polyethylene glycol (PEG). We found that the use of PEG led to compounds that were readily taken up by isolated mitochondria and by mitochondria inside cells. Within mitochondria the PEG linker greatly decreased adsorption of the TPP constructs to the matrix-facing face of the mitochondrial inner membrane. These findings will allow the distribution of mitochondria-targeted TPP compounds within mitochondria to be fine-tuned.

New Biocompatible β-Phosphorylated Linear Nitrones Targeting Mitochondria: Protective Effect in Apoptotic Cells.

The mitochondrion, an essential organelle involved in cellular respiration, energy production, and cell death, is the main cellular source of reactive oxygen species (ROS), including superoxide. Mitochondrial diseases resulting from uncontrolled/excess ROS generation are an emerging public health concern and there is current interest in specific mitochondriotropic probes to get information on in-situ ROS production. As such, nitrones vectorized by the triphenylphosphonium (TPP) cation have recently drawn attention despite reported cytotoxicity. Herein, we describe the synthesis of 13 low-toxic derivatives of N-benzylidene-1-diethoxyphosphoryl-1-methylethylamine N-oxide (PPN) alkyl chain-grafted to a pyridinium, triethylammonium or berberinium lipophilic cation. These nitrones showed in-vitro superoxide quenching activity and EPR/spin-trapping efficiency towards biologically relevant free radicals, including superoxide and hydroxyl radicals. Their mitochondrial penetration was confirmed by 31 P NMR spectroscopy, and their anti-apoptotic properties were assessed in Schwann cells treated with hydrogen peroxide. Two pyridinium-substituted PPNs were identified as potentially better alternatives to TPP nitrones conjugates for studying mitochondrial oxidative damage.

Enhanced protection against hypoxia/reoxygenation-induced apoptosis in H9c2 cells by puerarin-loaded liposomes modified with matrix metalloproteinases-targeting peptide and triphenylphosphonium

Based on the inhibition of mitochondrial permeability transition pore (mPTP) opening, puerarin (PUE) has a good potential to reduce myocardial ischemia/reperfusion injury (MI/RI). However, the lack of targeting of free PUE makes it difficult to reach the mitochondria. In this paper, we constructed matrix metalloproteinase-targeting peptide (MMP-TP) and triphenylphosphonium (TPP) cation co-modified liposomes loaded with PUE (PUE@T/M-L) for mitochondria-targeted drug delivery. PUE@T/M-L had a favorable particle size of 144.9 ± 0.8 nm, an encapsulation efficiency of 78.9 ± 0.6%, and a sustained-release behavior. The results of cytofluorimetric experiments showed that MMP-TP and TPP double-modified liposomes (T/M-L) enhanced intracellular uptake, escaped lysosomal capture, and promoted drug targeting into mitochondria. In addition, PUE@T/M-L enhanced the viability of hypoxia-reoxygenation (H/R) injured H9c2 cells by inhibiting mPTP opening and reactive oxygen species (ROS) production, reducing Bax expression and increasing Bcl-2 expression. It was inferred that PUE@T/M-L delivered PUE into the mitochondria of H/R injured H9c2 cells, resulting in a significant increase in cellular potency. Based on the ability of MMP-TP to bind the elevated expression of matrix metalloproteinases (MMPs), T/M-L had excellent tropism for Lipopolysaccharide (LPS) -stimulated macrophages and can significantly reduce TNF-α and ROS levels, thus allowing both drug accumulation in ischemic cardiomyocytes and reducing inflammatory stimulation during MI/RI. Fluorescence imaging results of the targeting effect using a DiR probe also indicated that DiR@T/M-L could accumulate and retain in the ischemic myocardium. Taken together, these results demonstrated the promising application of PUE@T/M-L for mitochondria-targeted drug delivery to achieve maximum therapeutic efficacy of PUE.