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Journal of Medicinal Chemistry Jul 2020Phosphine oxides and related phosphorus-containing functional groups such as phosphonates and phosphinates are established structural motifs that are still...
Phosphine oxides and related phosphorus-containing functional groups such as phosphonates and phosphinates are established structural motifs that are still underrepresented in today's drug discovery projects, and only few examples can be found among approved drugs. In this account, the physicochemical and properties of phosphine oxides and related phosphorus-containing functional groups are reported and compared to more commonly used structural motifs in drug discovery. Furthermore, the impact on the physicochemical properties of a real drug scaffold is exemplified by a series of phosphorus-containing analogs of imatinib. We demonstrate that phosphine oxides are highly polar functional groups leading to high solubility and metabolic stability but occasionally at the cost of reduced permeability. We conclude that phosphine oxides and related phosphorus-containing functional groups are valuable polar structural elements and that they deserve to be considered as a routine part of every medicinal chemist's toolbox.
Topics: Caco-2 Cells; Chemical Phenomena; Chemistry, Pharmaceutical; Drug Design; Drug Stability; Humans; Hydrophobic and Hydrophilic Interactions; Oxides; Permeability; Phosphines
PubMed: 32479078
DOI: 10.1021/acs.jmedchem.0c00407 -
Nature Aug 2021The substitution of an alkyl electrophile by a nucleophile is a foundational reaction in organic chemistry that enables the efficient and convergent synthesis of organic...
The substitution of an alkyl electrophile by a nucleophile is a foundational reaction in organic chemistry that enables the efficient and convergent synthesis of organic molecules. Although there has been substantial recent progress in exploiting transition-metal catalysis to expand the scope of nucleophilic substitution reactions to include carbon nucleophiles, there has been limited progress in corresponding reactions with nitrogen nucleophiles. For many substitution reactions, the bond construction itself is not the only challenge, as there is a need to control stereochemistry at the same time. Here we describe a method for the enantioconvergent substitution of unactivated racemic alkyl electrophiles by a ubiquitous nitrogen-containing functional group, an amide. Our method uses a photoinduced catalyst system based on copper, an Earth-abundant metal. This process for asymmetric N-alkylation relies on three distinct ligands-a bisphosphine, a phenoxide and a chiral diamine. The ligands assemble in situ to form two distinct catalysts that act cooperatively: a copper/bisphosphine/phenoxide complex that serves as a photocatalyst, and a chiral copper/diamine complex that catalyses enantioselective C-N bond formation. Our study thus expands enantioselective N-substitution by alkyl electrophiles beyond activated electrophiles (those bearing at least one sp- or sp-hybridized substituent on the carbon undergoing substitution) to include unactivated electrophiles.
Topics: Amides; Bromides; Carbon; Catalysis; Copper; Cyclization; Diamines; Ligands; Nitrogen; Phosphines; Photochemistry
PubMed: 34182570
DOI: 10.1038/s41586-021-03730-w -
Dalton Transactions (Cambridge, England... Jun 2022A novel synthesis of diphenyl(2-thienyl)phosphine, along with its' oxide, sulfide and selenide derivatives, is reported here. These phosphines have been characterized by...
A novel synthesis of diphenyl(2-thienyl)phosphine, along with its' oxide, sulfide and selenide derivatives, is reported here. These phosphines have been characterized by NMR, IR, MS and X-Ray crystallography. The phosphine oxide derivative was reacted with a selection of lanthanide(III) nitrates and triflates, LnX, to give the resultant metal-ligand complexes. These complexes have also been characterized by NMR, IR, MS and X-Ray crystallography. Single crystal X-Ray diffraction data shows a difference in metal-ligand complex stoichiometry and stereochemistry depending on the counteranion (nitrate triflate). The [Ln(ArPO)(NO)] ligand-nitrate complexes are nine-coordinate to the metal in the solid state (bidentate nitrate), featuring a 1 : 3 lanthanide-ligand ratio and bear an overall octahedral arrangement of the six, coordinated ligands. Our [Ln(ArPO)(NO)] ligand-nitrate complexes gave three examples of -stereochemistry, where -stereochemistry is almost universally observed in the literature of highly related [Ln(ArPO)(NO)] complexes. For the Tb complexes, two different arrangements of the ligands around the metal were observed in the solid state for [Tb(ArPO)(NO)] and [Tb(ArPO)(OTf)] [OTf]. [Tb(ArPO)(NO)] is strictly nine-coordinate, ligand -stereochemistry in the solid state, and [Tb(ArPO)(OTf)] [OTf] is strictly octahedral, six-coordinate, with a square-planar stereochemical arrangement of the phosphine oxide ligands around the metal.
Topics: Biphenyl Compounds; Coordination Complexes; Lanthanoid Series Elements; Ligands; Nitrates; Nitrogen Oxides; Oxides; Phosphines
PubMed: 35666488
DOI: 10.1039/d2dt01570f -
Journal of the American Chemical Society Dec 2021A highly enantioselective O-propargylation catalyzed by combining a phosphine-nickel complex and an axially chiral sodium dicarboxylate has been developed. The...
A highly enantioselective O-propargylation catalyzed by combining a phosphine-nickel complex and an axially chiral sodium dicarboxylate has been developed. The transformation features mild reaction conditions, a broad substrate scope, and excellent functional group tolerance, offering an efficient approach to an array of enantioenriched -propargyl hydroxylamines. Mechanistic studies support the presumed role of the chiral carboxylate as a counterion for nickel catalysis enabling the discovery of highly stereoselective transformations. The power of this reaction is illustrated by its application in the asymmetric total synthesis of potent firefly luciferase inhibitors and ()-dihydroyashabushiketol.
Topics: Alkylation; Alkynes; Catalysis; Coordination Complexes; Dicarboxylic Acids; Hydroxylamines; Models, Chemical; Nickel; Phosphines; Phthalimides; Stereoisomerism
PubMed: 34860020
DOI: 10.1021/jacs.1c11044 -
Journal of Labelled Compounds &... Nov 2022The synthesis of deuteriated tri-tert-butyl phosphine is reported. This synthesis is an adaptation of the known procedure for tri-tert-butyl phosphine via a Grignard...
The synthesis of deuteriated tri-tert-butyl phosphine is reported. This synthesis is an adaptation of the known procedure for tri-tert-butyl phosphine via a Grignard intermediate.
Topics: Molecular Structure; Phosphines
PubMed: 36041885
DOI: 10.1002/jlcr.4001 -
Water Research Jun 2024Phosphine (PH) is an important contributor to the phosphorus cycle and is widespread in various environments. However, there are few studies on PH in constructed...
Phosphine (PH) is an important contributor to the phosphorus cycle and is widespread in various environments. However, there are few studies on PH in constructed wetlands (CWs). In this study, lab-scale CWs and batch experiments were conducted to explore the characteristics and mechanisms of PH production in sulfur-based CWs. The results showed that the PH release flux of sulfur-based CWs varied from 0.86±0.04 ng·m·h to 1.88±0.09 ng·m·h. The dissolved PH was the main PH form in CWs and varied from 2.73 μg·L to 4.08 μg·L. The matrix-bound PH was a staging reservoir for PH and increased with substrate depth. In addition, the sulfur-based substrates had a significant improvement on PH production. Elemental sulfur is more conducive to PH production than pyrite. Moreover, there was a significant positive correlation between PH production, the dsrB gene, and nicotinamide adenine dinucleotide (NADH). NADH might catalyze the phosphate reduction process. And the final stage of the dissimilatory sulfate reduction pathway driven by the dsrB gene might also provide energy for phosphate reduction. The migration and transformation of PH increased the available P (Resin-P and NaHCO-P) from 35 % to 56 % in sulfur-based CW, and the P adsorption capacity was improved by 12 %. The higher proportion of available P increased the plant uptake rate of P by 17 %. This study improves the understanding of the phosphorus cycle in sulfur-based CW and provides new insight into the long-term stable operation of CWs.
Topics: Wetlands; Phosphines; Sulfur
PubMed: 38657306
DOI: 10.1016/j.watres.2024.121639 -
Chemistry (Weinheim An Der Bergstrasse,... Nov 2019Four cycloaurated phosphine sulfide complexes, [Au{κ -2-C H P(S)Ph } ][AuX ] [X=Cl (2), Br (3), I (4)] and [Au{κ -2-C H P(S)Ph } ]PF (5), have been prepared and...
Four cycloaurated phosphine sulfide complexes, [Au{κ -2-C H P(S)Ph } ][AuX ] [X=Cl (2), Br (3), I (4)] and [Au{κ -2-C H P(S)Ph } ]PF (5), have been prepared and thoroughly characterized. The compounds were found to be stable under physiological-like conditions and showed excellent cytotoxicity against a broad range of cancer cell lines and remarkable cytotoxicity in 3D tumor spheroids. Mechanistic studies with cervical cancer (HeLa) cells indicated that the cytotoxic effects of the compounds involve the inhibition of thioredoxin reductase and induction of apoptosis through mitochondrial disruption. In vivo experiments in nude mice bearing HeLa xenografts showed that treatment with compounds 4 and 5 resulted in significant inhibition of tumor growth (35.8 and 46.9 %, respectively), better than that of cisplatin (29 %). The newly synthesized gold complexes were also evaluated for their in vitro and in vivo anti-inflammatory activity through the study of lipopolysaccharide (LPS)-activated macrophages and carrageenan-induced hind paw edema in rats, respectively.
Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Apoptosis; Cell Survival; Cisplatin; Drug Screening Assays, Antitumor; Gold; Humans; Organogold Compounds; Phosphines; Sulfides
PubMed: 31414501
DOI: 10.1002/chem.201903388 -
Organic Letters Jul 2023An efficient palladium-catalyzed 2-fluoroallylation of P(O)H compounds with -difluorocyclopropanes is presented. The reaction provides a variety of 2-fluoroallylic...
An efficient palladium-catalyzed 2-fluoroallylation of P(O)H compounds with -difluorocyclopropanes is presented. The reaction provides a variety of 2-fluoroallylic phosphorus compounds in good yields with high selectivity through the sequential C-C bond activation, C-F bond cleavage, and C-P coupling process. Various H-phosphonates, H-phosphinates, and secondary phosphine oxides are all tolerated. In addition, the gram-scale synthesis and the late-stage modification of complex bioactive molecules show practical utilities of the transformation.
PubMed: 37435974
DOI: 10.1021/acs.orglett.3c01674 -
Journal of Inorganic Biochemistry Feb 2020Phosphonium salt (p-OCH-Ph)P(CHOH)Cl (MPOHC), derived phosphine ligands without and with SarGly (Sarcosine-Glycine) peptide carrier P(p-OCH-Ph)CHOH (MPOH) and...
Copper(I) complexes with phosphines P(p-OCH-Ph)CHOH and P(p-OCH-Ph)CHSarGly. Synthesis, multimodal DNA interactions, and prooxidative and in vitro antiproliferative activity.
Phosphonium salt (p-OCH-Ph)P(CHOH)Cl (MPOHC), derived phosphine ligands without and with SarGly (Sarcosine-Glycine) peptide carrier P(p-OCH-Ph)CHOH (MPOH) and P(p-OCH-Ph)CHSarGly (MPSG), respectively, and two copper(I) complexes [Cu(I)(dmp)(MPOH)] (1-MPOH; dmp = (2,9-dimethyl-1,10-phenanthroline)) and [Cu(I)(dmp)(MPSG)] (1-MPSG) were synthesized. The resulting compounds were characterized by elemental analysis, 1D and 2D NMR and UV-Vis absorption spectroscopies, mass spectrometry, cyclic voltammetry and by X-ray diffraction analysis. Cytotoxicity of all compounds was evaluated in vitro against colon, lung, breast, pancreatic, prostate tumor cell lines, as well as towards non-tumor cell lines: lung, kidney and keratinocyte. Stable in biological medium in the presence of atmospheric oxygen, Cu(I) complexes exerted a cytotoxic effect higher than that elicited by cisplatin against tested cancer cell lines. The introduction of methoxy group onto the phenyl rings of the phosphine ligand coordinated to the copper(I) ion resulted in a relevant increase of cytotoxicity in the case of breast, pancreatic and prostate tumor cell lines in vitro. Attachment of a peptide carrier significantly increased the selectivity towards cancer cells. Fluorescence spectroscopic data (calf thymus DNA: CT-DNA) titration), together with analysis of DNA fragmentation (gel electrophoresis) and molecular docking provided evidence for the multimodal interaction of copper compounds with DNA and showed their unusual low genotoxicity. Additionally, copper complexes were able to generate reactive oxygen species as a result of redox processes, proved by fluorescence spectroscopy and cyclic voltamperometry.
Topics: Antineoplastic Agents; Cell Proliferation; Coordination Complexes; Copper; DNA; Free Radicals; HEK293 Cells; Humans; MCF-7 Cells; Mutagens; Organometallic Compounds; Oxidative Stress; Peptides; Phosphines
PubMed: 31759264
DOI: 10.1016/j.jinorgbio.2019.110926 -
Life Sciences Sep 2019Poisoning with aluminium phosphide (AlP) commonly has a high rate of mortality and morbidities. Phosphine gas is the main cause of AlP poisoning that has deleterious...
AIMS
Poisoning with aluminium phosphide (AlP) commonly has a high rate of mortality and morbidities. Phosphine gas is the main cause of AlP poisoning that has deleterious effect on multi-organs especially heart, kidney, and liver. Furthermore, several studies reported that resveratrol has cytoprotective effects through its pleiotropic property. The purpose of this study was to estimate the dose-dependent role of resveratrol on phosphine induced acute hepatic toxicity in rat model.
MAIN METHODS
The rats have been exposed to LD of AlP (12 mg/kg) by gavage, and resveratrol doses (20, 40, and 80 mg/kg) were injected 30 min after intoxication. After 24 h, the serum and liver tissue were collected for present study.
KEY FINDINGS
The results indicated that phosphine causes an alteration in oxidative stress markers including elevation of ROS, and GSH level, MPO activity, reduction in SOD, catalase and G6PD activity as well as reduction in SOD1 and catalase expression. Furthermore, phosphine significantly induced phosphorylation of IkappaB, NF-kappaB and up-regulation of TNF-α, IL-1β, IL-6, and ICAM-1 expression. Also, phosphine induces markedly reduced hepatocytes lives cell and elevated apoptosis and necrosis. Co-treatment of resveratrol in a dose-dependent manner reversed aforementioned alterations. All in all, histological analysis indicated a deleterious effect of phosphine on the liver, which is mitigated by resveratrol administration.
SIGNIFICANCE
The results of the present study suggest targeting ROS/NF-kappaB signalling pathway by resveratrol may have a significant effect on the improvement of hepatic injury induced by phosphine. It also may be a possible candidate for the treatment of phosphine-poisoning.
Topics: Animals; Antioxidants; Apoptosis; Catalase; Chemical and Drug Induced Liver Injury; Hepatocytes; Inflammation; Interleukin-1beta; Liver; Male; NF-kappa B; Oxidative Stress; Phosphines; Phosphorylation; Rats; Rats, Wistar; Reactive Oxygen Species; Resveratrol; Signal Transduction; Tumor Necrosis Factor-alpha
PubMed: 31254582
DOI: 10.1016/j.lfs.2019.116607