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Biochemical and Biophysical Research... Feb 2021Treatment of neurodegenerative diseases, such as Parkinson's disease, Huntington's chorea, Alzheimer's disease, is one of the priority directions in modern medicine....
BACKGROUND
Treatment of neurodegenerative diseases, such as Parkinson's disease, Huntington's chorea, Alzheimer's disease, is one of the priority directions in modern medicine. Thus, search and production of new physiologically active substances for the treatment of neurodegenerative disorders is one of the most important tasks for organic chemistry. The approach based on the replacement of a peptide bond in a peptide molecule with a structural isostere, non-hydrolyzable methylene phosphoryl fragment makes it possible to increase the metabolic stability of peptide molecules to the destructive action of peptidases.
METHODS
This work is devoted to the approbation of a new synthetic approach to the production of physiologically active substances in a series of peptide-type compounds with activity by replacing the peptide bond with isosteric methylene-phosphoryl fragment with the preservation of the original amino acid sequence.
RESULTS
A phosphine analog of the known physiologically active tripeptide proline-glycine-proline was obtained, cytotoxicity and neuroprotective properties of the initial tripeptide and its phosphine analog were studied.
CONCLUSION
Preliminary biological tests have shown that the obtained phosphine analog of the proline-glycine-proline tripeptide is involved in modulating the formation of sediments in the cellular system of proteinopathy, which may indicate their potential antiaggregatory properties.
Topics: Cell Line, Tumor; Humans; Neurodegenerative Diseases; Neuroprotective Agents; Oligopeptides; Phosphines; Proline; Protein Aggregation, Pathological
PubMed: 33412416
DOI: 10.1016/j.bbrc.2020.12.087 -
European Journal of Medicinal Chemistry Nov 2021Given the increasing reports of well-defined bimetallic molecular complexes as potential anticancer agents in the last decades, along with the prevalence of platinum in... (Review)
Review
Given the increasing reports of well-defined bimetallic molecular complexes as potential anticancer agents in the last decades, along with the prevalence of platinum in anticancer therapy, we report here a detailed survey of bimetallic platinum and palladium complexes investigated as potential anticancer agents. Specifically, we will concentrate on the synthesis, characterisation and biological (anticancer) studies of a sub-class of these agents, namely homo and heterobimetallic complexes bearing a bridging phosphane ligand of the type: [LM(μ-RP(CH)PR)ML] (where M is platinum or palladium, M is any other transition metal, R = alkyl or aryl substituents, L or L are co-ligands, n = 1-6). We will review the in vitro and in vivo activities and any mechanistic anticancer studies of these complexes with a view of trying to delineate patterns in biological activity and structure-activity relationships (SAR). We do not include the review of bimetallic complexes in this class that have not undergone any anticancer testing, nor those that have been involved in other biological investigations unrelated to cancer studies.
Topics: Animals; Antineoplastic Agents; Cell Survival; Coordination Complexes; Humans; Ligands; Palladium; Phosphines; Platinum; Structure-Activity Relationship
PubMed: 34214843
DOI: 10.1016/j.ejmech.2021.113651 -
Accounts of Chemical Research Dec 2022This Account presents an overview of a promising collection of phosphine ligands simply made from the modular Fischer indolization process and their applications in...
This Account presents an overview of a promising collection of phosphine ligands simply made from the modular Fischer indolization process and their applications in modern arylation processes. Using one easily accessible 2-arylindole scaffold, three major phosphino-moiety-positioned ligand series can be readily generated. We have attempted to explore challenging electrophilic and nucleophilic partners for the coupling reaction using the modular ligand tool. For the electrophilic partner study, -type ligands, where the phosphino group is located at the 2-arene position of 2-arylindole, allow the successful cross-coupling of aryl mesylates. The ligand forms a palladacycle before entering the cross-coupling catalytic cycle. For the nucleophilic partner investigation, the indole C3-positioned phosphines show the first accomplishment of Pd-catalyzed organotitanium nucleophile arylation. Indeed, the aryl-titanium nucleophile undergoes cross-coupling more efficiently than does the organoboron coupling partner in particular cases. Moreover, in the indole C3-positioned phosphine series, the -PPh-containing ligands perform better in the highly sterically hindered cross-coupling of aryl chlorides than do ligands containing the -PCy moiety. The catalyst loading can even be reduced to 0.2 mol % Pd for tetra--substituted biaryl synthesis. This finding offers a new perspective on the next-generation design of phosphine ligands in which the sterically bulky and electron-rich -PR group (R = alkyl) may not be necessary for the cross-coupling of aryl chlorides. In general, we hypothesize that a good balance of steric and electronic properties for entertaining the oxidative addition and reductive elimination steps is crucial to the success of the reaction. For the steric factor, the highly sterically congested -PR group normally favors the reductive elimination, yet we conjecture that this sterically bulky group would serve as an obstacle for the incoming aryl halides. For the electronic factor, the electron rich -PR group is believed to support the oxidative cleavage of the C(Ar)-Cl bond by donating more electron density to the corresponding σ* orbital. Nevertheless, the high electron richness of the -PR group may disfavor the reductive elimination electronically. Overall, an appropriate balance of both electron density and steric bulkiness is suggested to allow the sterically hindered cross-coupling to proceed smoothly. We have found that the -PPh-containing ligand is a good starting point for this investigation. The formation of aromatic carbon-carbon (C-C) and carbon-heteroatom (C-X) bonds from aryl chlorides was successfully realized using our proprietary phosphines.In addition to the indole-core-bearing ligand skeleton, we also explored the relevant imidazolyl and carbazolyl phosphines for their unique applications. Interestingly, the carbazolyl ligand, having more flexible C-N axial chirality, displays particular interchangeable Pd-N and Pd-arene coordination, which facilitates both oxidative addition and reductive elimination processes. Moreover, this C-N axially chiral ligand allows the successful asymmetric Suzuki-Miyaura coupling for attaining the most sterically hindered tetra--substituted biaryls with excellent enantioselectivity. The rationale behind these scientifically interesting findings is presented in detail.
Topics: Ligands; Palladium; Phosphines; Chlorides; Indoles; Carbon
PubMed: 36472355
DOI: 10.1021/acs.accounts.2c00587 -
Drug Research Feb 2022Aluminum phosphide (AlP) toxicity is associated with a high risk of death due to heart, liver, and kidney failure as the target organs. Phosphine gas released due to the...
BACKGROUND
Aluminum phosphide (AlP) toxicity is associated with a high risk of death due to heart, liver, and kidney failure as the target organs. Phosphine gas released due to the ingestion is the main factor involved in the multi-organ failure with various mechanisms. Levosimendan (LEV) is a calcium sensitizer with a pleiotropic effect on multiple organs. This study aimed to investigate whether LEV can alleviate AlP-induced nephrotoxicity in the rat model.
METHOD
Six groups included control group (almond oil only), sole LEV group (48 µg/kg), AlP group (LD50=10 µg/kg), and the poisoned groups treated with LEV at doses of 12, 24, and 48 µg/kg 30 min after AlP gavage. After 24 hours of treatment, serum and kidney samples were taken for biochemical and histopathological analyses.
RESULT
Biochemical analysis of the AlP group showed that the activity of complexes I, II, and IV was significantly reduced, while the levels of lipid peroxidation (LPO) and reactive oxygen species (ROS), lactate, and myeloperoxidase (MPO) activity significantly increased. Also, AlP reduced live renal cells and elevated necrosis. However, the levels of serum creatinine and blood urea nitrogen were not affected by the poisoning. LEV co-treatment could increase mitochondrial complex activity and reduce MPO activity, LPO, ROS, and lactate levels. Additionally, the histopathological analysis showed the detrimental effects of AlP on kidney tissue, which was mitigated by LEV administration.
CONCLUSION
Our findings showed that LEV can potentially improve oxidative stress, imbalance in the redox status, necrosis, and pathological injuries in kidney tissue following AlP-poisoning.
Topics: Animals; Heart; Kidney; Oxidative Stress; Phosphines; Rats; Reactive Oxygen Species; Simendan
PubMed: 34788887
DOI: 10.1055/a-1661-5439 -
Scientific Reports May 2023The use of metal phosphides, particularly aluminum phosphide, poses a significant threat to human safety and results in high mortality rates. This study aimed to...
The use of metal phosphides, particularly aluminum phosphide, poses a significant threat to human safety and results in high mortality rates. This study aimed to determine mortality patterns and predictive factors for acute zinc and aluminum phosphide poisoning cases that were admitted to Menoufia University Poison and Dependence Control Center from 2017 to 2021. Statistical analysis revealed that poisoning was more common among females (59.7%), aged between 10 and 20 years, and from rural regions. Most cases were students, and most poisonings were the result of suicidal intentions (78.6%). A new hybrid model named Bayesian Optimization-Relevance Vector Machine (BO-RVM) was proposed to forecast fatal poisoning. The model achieved an overall accuracy of 97%, with high positive predictive value (PPV) and negative predictive value (NPV) values of 100% and 96%, respectively. The sensitivity was 89.3%, while the specificity was 100%. The F1 score was 94.3%, indicating a good balance between precision and recall. These results suggest that the model performs well in identifying both positive and negative cases. Additionally, the BO-RVM model has a fast and accurate processing time of 379.9595 s, making it a promising tool for various applications. The study underscores the need for public health policies to restrict the availability and use of phosphides in Egypt and adopt effective treatment methods for phosphide-poisoned patients. Clinical suspicion, positive silver nitrate test for phosphine, and analysis of cholinesterase levels are useful in diagnosing metal phosphide poisoning, which can cause various symptoms.
Topics: Female; Humans; Child; Adolescent; Young Adult; Adult; Aluminum; Bayes Theorem; Phosphines; Aluminum Compounds; Poisons; Heavy Metal Poisoning; Poisoning; Pesticides
PubMed: 37217491
DOI: 10.1038/s41598-023-34489-x -
Molecules (Basel, Switzerland) Mar 2023Organoruthenium pyrithione (1-hydroxypyridine-2-thione) complexes have been shown in our recent studies to be a promising family of compounds for development of new...
Organoruthenium pyrithione (1-hydroxypyridine-2-thione) complexes have been shown in our recent studies to be a promising family of compounds for development of new anticancer drugs. The complex [(η--cymene)Ru(pyrithionato)(pta)]PF contains phosphine ligand pta (1,3,5-triaza-7-phosphaadamantane) as a functionality that improves the stability of the complex and its aqueous solubility. Here, we report our efforts to find pta alternatives and discover new structural elements to improve the biological properties of ruthenium anticancer drugs. The pta ligand was replaced by a selection of phosphine, phosphite, and arsine ligands to identify new functionalities, leading to improvement in inhibitory potency towards enzyme glutathione -transferase. In addition, cytotoxicity in breast, bone, and colon cancers was investigated.
Topics: Ruthenium; Ruthenium Compounds; Phosphines; Antineoplastic Agents; Organometallic Compounds; Coordination Complexes; Cell Line, Tumor
PubMed: 36985471
DOI: 10.3390/molecules28062499 -
Marine Pollution Bulletin Aug 2021Organophosphorus derivatives are widely used in human health care and have been detected in aquatic ecosystems. These compounds may pose significant risks to non-target...
Toxicity assessment of organophosphorus in Ruditapes decussatus via physiological, chemical and biochemical determination: A case study with the compounds γ-oximo- and γ-amino-phosphonates and phosphine oxides.
Organophosphorus derivatives are widely used in human health care and have been detected in aquatic ecosystems. These compounds may pose significant risks to non-target exposed organisms and only limited studies are available on bioconcentration and the effects of organophosphorus derivatives on marine organisms. The aim of this work was to evaluate the possible toxic effects of two concentrations (20 and 40 μg/L) of γ-oximo- and γ-amino-phosphonates and phosphine oxides in mediterranean clams Ruditapes decussatus exposed for 14 days using different biomarkers and the changes of filtration and respiration rate. The use of clams in ecotoxicity evaluation is thus mandatory to assess the feasibility of assessing oxidative stress on R. decussatus after being exposed to γ-oximo- and γ-amino-phosphonates and phosphine oxides. The oxidative status was analyzed by measuring oxidative stress biomarkers RNS and ROS production in mitochondria, superoxide dismutase (SOD), catalase (CAT), glutathione-S-transferases (GSTs), lipid peroxidation (LPO) and acetylcholinesterase (AChE), whose alteration was indicative of organophosphorus exposure, in both gills and digestive gland of the clams. No significant alterations in RNS, ROS production, SOD, CAT and AChE activities and MDA content were observed in both organs of clams treated with γ-oximophosphine oxides. It was possible then to hypothesize that γ-oximophosphine oxides may have probably exerted an incomplete alteration of antioxidant defenses and damage, which was changed by the activation of defense mechanisms. On the contrary, oxidative stress parameters were changed after exposure to γ-amino-phosphonates and phosphine oxides. In addition, metals accumulation, filtration and respiration rates were altered following exposure to all the studied organophosphorus compounds.
Topics: Animals; Biomarkers; Bivalvia; Catalase; Ecosystem; Gills; Lipid Peroxidation; Organophosphonates; Oxidative Stress; Oxides; Phosphines; Superoxide Dismutase; Water Pollutants, Chemical
PubMed: 34082359
DOI: 10.1016/j.marpolbul.2021.112556 -
Molecules (Basel, Switzerland) Mar 2020Phosphine resistance is a worldwide issue threatening the grain industry. The cuticles of insects are covered with a layer of lipids, which protect insect bodies from...
Preliminary Study on the Differences in Hydrocarbons Between Phosphine-Susceptible and -Resistant Strains of (Fabricius) and (Herbst) Using Direct Immersion Solid-Phase Microextraction Coupled with GC-MS.
Phosphine resistance is a worldwide issue threatening the grain industry. The cuticles of insects are covered with a layer of lipids, which protect insect bodies from the harmful effects of pesticides. The main components of the cuticular lipids are hydrocarbon compounds. In this research, phosphine-resistant and -susceptible strains of two main stored-grain insects, and , were tested to determine the possible role of their cuticular hydrocarbons in phosphine resistance. Direct immersion solid-phase microextraction followed by gas chromatography-mass spectrometry (GC-MS) was applied to extract and analyze the cuticular hydrocarbons. The results showed significant differences between the resistant and susceptible strains regarding the cuticular hydrocarbons that were investigated. The resistant insects of both species contained higher amounts than the susceptible insects for the majority of the hydrocarbons, sixteen from cuticular extraction and nineteen from the homogenized body extraction for and eighteen from cuticular extraction and twenty-one from the homogenized body extraction for . 3-methylnonacosane and 2-methylheptacosane had the highest significant difference between the susceptible and resistant strains of from the cuticle and the homogenized body, respectively. Unknown5 from the cuticle and 3-methylhentriacontane from the homogenized body recorded the highest significant differences in . The higher hydrocarbon content is a key factor in eliminating phosphine from entering resistant insect bodies, acting as a barrier between insects and the surrounding phosphine environment.
Topics: Alkanes; Animals; Coleoptera; Complex Mixtures; Edible Grain; Gas Chromatography-Mass Spectrometry; Insecticide Resistance; Insecticides; Integumentary System; Phosphines; Solid Phase Microextraction; Tribolium; Triticum
PubMed: 32235326
DOI: 10.3390/molecules25071565 -
Dalton Transactions (Cambridge, England... Jul 2024The search for new metal-based anticancer drug candidates is a fundamental task in medicinal inorganic chemistry. In this work, we assessed the potential of two new...
The search for new metal-based anticancer drug candidates is a fundamental task in medicinal inorganic chemistry. In this work, we assessed the potential of two new Ru(II)-phosphine-mercapto complexes as potential anticancer agents. The complexes, with the formula [Ru(bipy)(dppen)(Lx)]PF [(1), HL1 = 2-mercapto-pyridine and (2), HL2 = 2-mercapto-pyrimidine, bipy = 2,2'-bipyridine, dppen = -1,2-bis(diphenylphosphino)-ethylene] were synthesized and characterized by nuclear magnetic resonance (NMR) [H, P(H), and C], high resolution mass spectrometry (HR-MS), cyclic voltammetry, infrared and UV-Vis spectroscopies. Complex 2 was obtained as a mixture of two isomers, 2a and 2b, respectively. The composition of these metal complexes was confirmed by elemental analysis and liquid chromatography-mass spectrometry (LC-MS). To obtain insights into their lipophilicity, their distribution coefficients between -octanol/PBS were determined. Both complexes showed affinity mainly for the organic phase, presenting positive log values. Also, their stability was confirmed over 48 h in different media (, DMSO, PBS and cell culture medium) HPLC, UV-Vis and P{H} NMR spectroscopies. Since enzymes from the P-450 system play a crucial role in cellular detoxification and metabolism, the microsomal stability of 1, which was found to be the most interesting compound of this study, was investigated using human microsomes to verify its potential oxidation in the liver. The analyses by LC-MS and ESI-MS reveal three main metabolites, obtained by oxidation in the dppen and bipy moieties. Moreover, 1 was able to interact with human serum albumin (HSA). The cytotoxicity of the metal complexes was tested in different cancerous and non-cancerous cell lines. Complex 1 was found to be more selective than cisplatin against MDA-MB-231 breast cancer cells when compared to MCF-10A non-cancerous cells. In addition, complex 1 affects cell morphology and migration, and inhibits colony formation in MDA-MB-231 cells, making it a promising cytotoxic agent against breast cancer.
Topics: Humans; Antineoplastic Agents; Phosphines; Ruthenium; Coordination Complexes; Cell Line, Tumor; Sulfhydryl Compounds; Cell Proliferation; Cell Survival; Drug Screening Assays, Antitumor; Molecular Structure
PubMed: 38895770
DOI: 10.1039/d4dt01191k -
Inorganic Chemistry May 2022Heterobimetallic complexes have attracted much interest due to their broad range of structures and reactivities as well as unique catalytic abilities. Additionally,...
Heterobimetallic complexes have attracted much interest due to their broad range of structures and reactivities as well as unique catalytic abilities. Additionally, these complexes can be utilized as single-source precursors for the synthesis of binary intermetallic compounds. An example is the family of bis(pyridine-2-thiolato)dichloro-germanium and tin complexes of group 10 metals (Pd and Pt). The reactivity of these heterobimetallic complexes is highly tunable through substitution of the group 14 element and the neutral ligand bound to the transition metal. Here, we study the binding energies of three different phosphorous-based ligands, PR (R = Bu, Ph, and OPh) by density functional theory and restricted Hartree-Fock methods. The PR ligand-binding energies follow the trend of PBu > PPh > P(OPh), in agreement with their sigma-bonding ability. These results are confirmed by ligand exchange experiments monitored with P NMR spectroscopy, in which a weaker binding PR ligand is replaced with a stronger one. Furthermore, we demonstrate that the heterobimetallic complexes are active catalysts in the Negishi coupling reaction, where stronger binding PR ligands inhibit access to an active site at the metal center. Similar strategies could be applied to other complexes to better understand their ligand-binding energetics and predict their reactivity as both precursors and catalysts.
Topics: Germanium; Ligands; Phosphines; Transition Elements
PubMed: 35481778
DOI: 10.1021/acs.inorgchem.2c00229