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In this study, [(N-benzamidomethyl)(N-benzoyl)amino]methyltriphenylphosphonium tetrafluoroborate was synthesized at 80 °C, starting from N-benzoylaminomethyltriphenylphosphonium tetrafluoroborate, by a specific α-amidoalkylation reaction using Hünig's base as a catalyst. N-benzoylaminomethyltriphenylphosphonium tetrafluoroborate acts as both an amidoalkylating agent and a nucleophile precursor. The structure of the compound obtained was confirmed by spectroscopic methods (1H-, 13C-, 31P-NMR, IR) and HR-MS analysis. [ABSTRACT FROM AUTHOR]

Mono‐ and bis‐pyridinium, phosphonium and sulfonium allylic salts, containing adamantane fragment, have been obtained from the substitution reaction in 1,4‐dibromo‐2‐butene. It was found, that the attack of triethylamine undergoes from the sterically less hindered side, leading to deprotonation and subsequent elimination of the molecular fragment with the formation of a new salt of diene structure. Quantum chemical calculations were used to confirm the structure of one of the products by correlation analysis of experimental and calculated NMR data that confirmed the s‐cisoid conformation of the diene. It was found, that obtained dienes may be used as substrates in Diels‐Alder reaction despite their high sterical hinderance. [ABSTRACT FROM AUTHOR]

In this study, [(N-benzamidomethyl)(N-benzoyl)amino]methyltriphenylphosphonium tetrafluoroborate was synthesized at 80 °C, starting from N-benzoylaminomethyltriphenylphosphonium tetrafluoroborate, by a specific α-amidoalkylation reaction using Hünig’s base as a catalyst. N-benzoylaminomethyltriphenylphosphonium tetrafluoroborate acts as both an amidoalkylating agent and a nucleophile precursor. The structure of the compound obtained was confirmed by spectroscopic methods (1H-, 13C-, 31P-NMR, IR) and HR-MS analysis.

The most important area of modern pharmacology is the targeted delivery of drugs, and one of the most promising classes of chemical compounds for creating drugs of this kind are the photochromic spiropyrans, capable of light-controlled biological activity. This work is devoted to the synthesis and study of the photochromic properties of new triphenylphosphonium salts of spiropyrans. It was found that all the synthesized cationic spiropyrans have high photosensitivity, increased resistance to photodegradation and the ability for photoluminescence. [ABSTRACT FROM AUTHOR]

DNA chains with sequential guanine (G) repeats can lead to the formation of G-quadruplexes (G4), which are found in functional DNA and RNA regions like telomeres and oncogene promoters. The development of molecules with adequate structural features to selectively stabilize G4 structures can counteract cell immortality, highly described for cancer cells, and also downregulate transcription events underlying cell apoptosis and/or senescence processes. We describe here, the efficiency of four highly charged porphyrins-phosphonium conjugates to act as G4 stabilizing agents. The spectrophotometric results allowed to select the conjugates P2-PPh 3 and P3-PPh 3 as the most promising ones to stabilize selectively G4 structures. Molecular dynamics simulation experiments were performed and support the preferential binding of P2-PPh 3 namely to MYC and of P3-PPh 3 to KRAS. The ability of both ligands to block the activity of Taq polymerase was confirmed and also their higher cytotoxicity against the two melanoma cell lines A375 and SK-MEL-28 than to immortalized skin keratinocytes. Both ligands present efficient cellular uptake, nuclear co-localization and high ability to generate 1O 2 namely when interacting with G4 structure. The obtained data points the synthesized porphyrins as promising ligands to be used in a dual approach that can combine G4 stabilization and Photodynamic therapy (PDT). • New porphyrin-triphenylphosphonium (Px-PPh 3) conjugates, owing 4 to 8+ positive charges, were synthesized • P2-PPh 3 and P3-PPh 3 conjugates showed high affinity and selectivity for G-quadruplexes (G4) and end-stacking binding mode on the top of G4 • PCR stop assays revealed the ability of P2-PPh 3 and P3-PPh 3 conjugates to block Taq polymerase activity • P2-PPh 3 and P3-PPh 3 showed greater cytotoxic effect, efficient cellular uptake in melanoma cells and nuclear co-localization • P2-PPh 3 and P3-PPh 3 conjugates are promising candidates with ability to compromise tumor cells proliferation [ABSTRACT FROM AUTHOR]

A series of novel triphenylphosphonium derivatives of 1,3-oxazole containing at C2 and C5-positions electron withdrawing or electron-donating groups were synthesized and characterized by 1H, 31P NMR and IR spectroscopy, element analysis and chromato-mass spectrometry. These compounds were found to be a new class of non-peptide inhibitors of furin. Depending on the chemical structure, they inactivated enzyme at micromolar level by mechanism of competitive, non-competitive or mixed inhibition. Evaluation of the synthesized derivatives as furin inhibitors showed that among the triphenylphosphonium salts studied by us, oxazole 12 containing 2,4-dichlorophenyl- in the C2-position and MeS-group at C5 is the most active (Ki = 1.57 μM) competitive inhibitor of furin. Our results provided evidence that chemical modification of 1,3-oxazole-4-yl-triphenylphosphonium salts may be useful for developing new more potent and selective inhibitors of furin.

Abstract: The present work aims at identifying new ion channel modulators able to target mitochondrial ATP-sensitive potassium channels (mitoKATP channels). An innovative approach should consist in fixing a cationic and hydrophobic triphenylphosphonium fragment on the structure of known KATP channel openers. Such phosphonium salts are expected to cross the biological membranes and to accumulate into mitochondria. Previous works revealed that the presence of an (R)-1-hydroxy-2-propylamino chain at the 3-position of 4H-1,2,4-benzothiadiazine 1,1-dioxides KATP channel openers increased, in most cases, the selectivity towards the pancreatic-type (SUR1/Kir6.2) KATP channel. In order to target cardiac mitoKATP channels, we decided to introduce a triphenylphosphonium group through an ester link on the SUR1-selective (R)-7-chloro-3-(1-hydroxy-2-propyl)amino-4H-1,2,4-benzothiadiazine 1,1-dioxide. The new compounds were found to preserve an inhibitory activity on insulin secretion (SUR1-type KATP channel openers) while no clear demonstration of an impact on mitochondria from cardiomyocytes (measurement of oxygen consumption, respiratory parameters and ATP production on H9C2 cells) was observed. However, the most active (inhibition of insulin release) compound 17 was found to penetrate the cardiac cells and to reach mitochondria. [Copyright &y& Elsevier]

Mitochondrial research is presently one of the fastest growing disciplines in biomedicine. Since the early 1990s, it has become increasingly evident that mitochondrial dysfunction contributes to a large variety of human disorders, ranging from neurodegenerative and neuromuscular diseases, obesity, and diabetes to ischemia-reperfusion injury and cancer. Most remarkably, mitochondria, the “power house” of the cell, have also become accepted as the “motor of cell death” reflecting their recognized key role during apoptosis. Based on these recent exciting developments in mitochondrial research, increasing pharmacological efforts have been made leading to the emergence of “Mitochondrial Medicine” as a whole new field of biomedical research. The identification of molecular mitochondrial drug targets in combination with the development of methods for selectively delivering biologically active molecules to the site of mitochondria will eventually launch a multitude of new therapies for the treatment of mitochondria-related diseases, which are based either on the selective protection, repair, or eradication of cells. Yet, while tremendous efforts are being undertaken to identify new mitochondrial drugs and drug targets, the development of mitochondria-specific drug carrier systems is lagging behind. To ensure a high efficiency of current and future mitochondrial therapeutics, colloidal vectors, i.e., delivery systems, need to be developed able to selectively transport biologically active molecules to and into mitochondria within living human cells. Here we review ongoing efforts in our laboratory directed toward the development of different phospholipid- and non-phospholipid-based mitochondriotropic drug carrier systems. [ABSTRACT FROM AUTHOR]

Mitochondrial dysfunction contributes to a large variety of human disorders, ranging from neurodegenerative and neuromuscular diseases, obesity, and diabetes to ischemia-reperfusion injury and cancer. Increasing pharmacological efforts toward therapeutic interventions have been made leading to the emergence of “Mitochondrial Medicine” as a new field of biomedical research. The identification of molecular mitochondrial drug targets in combination with the development of methods for selectively delivering biologically active molecules to the site of mitochondria will eventually launch a multitude of new therapies for the treatment of mitochondria-related diseases, which are based either on the selective protection, repair, or eradication of cells. Yet, while tremendous efforts are being undertaken to identify new mitochondrial drugs and drug targets, the development of mitochondria-specific drug carrier systems is lagging behind. To ensure a high efficiency of current and future mitochondrial therapeutics, delivery systems need to be developed, which are able to selectively transport biologically active molecules to and into mitochondria within living human cells. In this study we present the first data demonstrating that conventional liposomes can be rendered mitochondria-specific via the attachment of known mitochondriotropic residues to the liposomal surface. [ABSTRACT FROM AUTHOR]

Virtual high throughput screening (VHTS) was performed to assess possible interactions which might occur between commercially available triphenylphosphonium (TPP) cations and estrogen receptor alpha (ERalpha) that could be exploited to design novel ERalpha modulators. One application of TPP cations is for delivering bioactive molecules to targets in mitochondria as the large membrane potential of mitochondria leads cations to accumulate inside them. The estrogen receptors (ERs) alpha and beta, normally activated by the endogenous hormone 17beta-estradiol, are responsible for controlling transcription of nuclear DNA necessary for human development and reproduction. ERs are also associated with the plasma membrane and have been found in the mitochondria of a variety of cell types. Selective estrogen receptor modulators (SERMs) are synthetic compounds which are used to modulate ER activity. Different SERMs display varying combinations of agonistic, antagonistic and neutral effects upon estrogen receptors depending upon the tissue type and cellular location of the receptor. Thus, they are being employed to treat a range of ER-related disorders. A common feature shared by many SERMs is the close arrangement of three aromatic rings similar to TPP cations. Given this structural similarity, the estrogenic activity of triphenyl phosphonium salts was investigated using the automated docking program eHiTS. Compounds were docked into ten different crystal structures of ERalpha. Structures were chosen based upon eHiTS ability to accurately identify the majority of estrogenically active compounds given a set of active and decoy molecules. The results of the VHTS suggest hybrids of TPP cations and known SERMs could serve as potent mitochondrial SERMs.