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ACS Pharmacology & Translational Science Aug 2020Drugs that contain phosphates (and phosphonates or phosphinates) have intrinsic absorption issues and are therefore often delivered in prodrug forms to promote their... (Review)
Review
Drugs that contain phosphates (and phosphonates or phosphinates) have intrinsic absorption issues and are therefore often delivered in prodrug forms to promote their uptake. Effective prodrug forms distribute their payload to the site of the intended target and release it efficiently with minimal byproduct toxicity. The ability to balance unwanted payload release during transit with desired release at the site of action is critical to prodrug efficacy. Despite decades of research on prodrug forms, choosing the ideal prodrug form remains a challenge which is often solved empirically. The recent emergency use authorization of the antiviral remdesivir for COVID-19 exemplifies a new approach for delivery of phosphate prodrugs by parenteral dosing, which minimizes payload release during transit and maximizes tissue payload distribution. This review focuses on the role of metabolic activation in efficacy during oral and parenteral dosing of phosphate, phosphonate, and phosphinate prodrugs. Through examining prior structure-activity studies on prodrug forms and the choices that led to development of remdesivir and other clinical drugs and drug candidates, a better understanding of their ability to distribute to the planned site of action, such as the liver, plasma, PBMCs, or peripheral tissues, can be gained. The structure-activity relationships described here will facilitate the rational design of future prodrugs.
PubMed: 32821882
DOI: 10.1021/acsptsci.0c00076 -
Biochemistry Sep 2020Protein biochemistry protocols typically include disulfide bond reducing agents to guard against unwanted thiol oxidation and protein aggregation. Commonly used...
Protein biochemistry protocols typically include disulfide bond reducing agents to guard against unwanted thiol oxidation and protein aggregation. Commonly used disulfide bond reducing agents include dithiothreitol, β-mercaptoethanol, glutathione, and the tris(alkyl)phosphine compounds tris(2-carboxyethyl)phosphine (TCEP) and tris(3-hydroxypropyl)phosphine (THPP). While studying the catalytic activity of the NAD(P)H-dependent enzyme Δ-pyrroline-5-carboxylate reductase, we unexpectedly observed a rapid non-enzymatic chemical reaction between NAD and the reducing agents TCEP and THPP. The product of the reaction exhibits a maximum ultraviolet absorbance peak at 334 nm and forms with an apparent association rate constant of 231-491 M s. The reaction is reversible, and nuclear magnetic resonance characterization (H, C, and P) of the product revealed a covalent adduct between the phosphorus of the tris(alkyl)phosphine reducing agent and the C4 atom of the nicotinamide ring of NAD. We also report a 1.45 Å resolution crystal structure of short-chain dehydrogenase/reductase with the NADP-TCEP reaction product bound in the cofactor binding site, which shows that the adduct can potentially inhibit enzymes. These findings serve to caution researchers when using TCEP or THPP in experimental protocols with NAD(P). Because NAD(P)-dependent oxidoreductases are widespread in nature, our results may be broadly relevant.
Topics: Bacterial Proteins; Burkholderia; Disulfides; Dithiothreitol; NAD; Oxidation-Reduction; Phosphines; Protein Conformation; Protein Domains; Reducing Agents; Short Chain Dehydrogenase-Reductases
PubMed: 32841567
DOI: 10.1021/acs.biochem.0c00490 -
Nature Communications Nov 2022The development of general catalytic methods for the regio- and stereoselective construction of phosphoryl derivatives from identical substrates remains a formidable...
The development of general catalytic methods for the regio- and stereoselective construction of phosphoryl derivatives from identical substrates remains a formidable challenge in organic synthesis. Enabled by the newly developed BDPP-type ligands, we disclosed a nickel-catalyzed allenylation of phosphine oxides rationally and predictably, allowing the construction of versatile chiral allenylphosphoryl derivatives with high enantiopurity (up to 94% e.e.). Alternatively, using an achiral phosphine ligand dcypbz under acidic conditions, we achieved a regiochemical switch of the 1,3-dienylation to afford functionalized phosphinoyl 1,3-butadienes (up to 93% yield). The salient features of this method include switchable reactivity, broad substrate scope, readily available feedstock, single-step preparation, and high asymmetric induction.
Topics: Nickel; Oxides; Stereoisomerism; Catalysis; Ligands
PubMed: 36396661
DOI: 10.1038/s41467-022-34764-x -
Insects Dec 2020In this study, we evaluated nitrogen treatment on phosphine-resistant field and -susceptible laboratory populations of different stored product beetles. Nine trials were...
In this study, we evaluated nitrogen treatment on phosphine-resistant field and -susceptible laboratory populations of different stored product beetles. Nine trials were conducted in commercial nitrogen chambers with the O level set at 1.0%. Two different temperatures-i.e., 28 and 40 °C-and three exposure intervals-i.e., 2.5, 3 and 9 d-were used in our tests. Adults of the sawtoothed grain beetle, (L.) (Coleoptera: Silvanidae); the red flour beetle, (Herbst) (Coleoptera: Tenebrionidae); and the rice weevil, (L.) (Coleoptera: Curculionidae) were used in the trials. The insects were placed in vials with different commodities per species and population, and their mortality was measured after the termination of each trial. Then, the vials were kept in incubator chambers at 25 °C and 65% relative humidity for 65 d to measure progeny production. Complete parental mortality was observed in all cases for and , but there was some survival for at 28 °C and 3 d of exposure. In general, progeny production was completely (100%) suppressed, with some exceptions for all species and populations. The results indicate that low oxygen is effective for all species tested, regardless of their resistance status to phosphine, and can be further adopted as an alternative method to mitigate resistance in stored product beetles.
PubMed: 33333765
DOI: 10.3390/insects11120885 -
JPMA. the Journal of the Pakistan... Jun 2021Wheat pill (zinc or aluminium phosphide), also known as rice pill, is used as rodenticide in wheat and rice storage reservoirs. In developing countries such as Pakistan...
Wheat pill (zinc or aluminium phosphide), also known as rice pill, is used as rodenticide in wheat and rice storage reservoirs. In developing countries such as Pakistan there has been an increase in the number of aluminium phosphide (wheat pill) poisoning with suicidal intent due to its easy accessibility. It has a high mortality rate, with no antidote available. A young female presented with classical signs and symptoms of wheat pill poisoning, although during her stay at the hospital she developed cardiac arrhythmias leading to shock, haematuria, pleural effusion, and hyperglycaemia due to acute pancreatitis. Due to the appropriate recognition and management of the complications, the patient was able to recuperate. Appropriate transfer to Intensive Care Unit and prompt recognition of complications can lead to good outcomes. We recommend that there should be a nationwide cognizance campaign regarding the lethal consequences of wheat pill consumption by humans and proper disposal of this deadly material.
Topics: Acute Disease; Aluminum Compounds; Female; Humans; Pakistan; Pancreatitis; Phosphines; Poisoning; Triticum
PubMed: 34111096
DOI: 10.47391/JPMA.02-222 -
Acta Crystallographica. Section E,... Feb 2021Palladium 2-di-cyclo-hexyl-phosphanyl-2',6'-diisopropoxybiphenyl (Pd-RuPhos) catalysts demonstrate high catalytic activity for Negishi cross-couplings of sterically...
Palladium 2-di-cyclo-hexyl-phosphanyl-2',6'-diisopropoxybiphenyl (Pd-RuPhos) catalysts demonstrate high catalytic activity for Negishi cross-couplings of sterically hindered aryl halides, for Suzuki-Miyaura cross-couplings of tosyl-ated olefins, and for Buchwald-Hartwig amination of sterically hindered amines. The solid-state structure of the free RuPhos ligand, CHOP, is reported herein for the first time. RuPhos crystallizes in a triclinic cell containing two independent mol-ecules of the phosphine without any lattice solvent. Pertinent bond metrics and comparisons to other phosphine ligands are presented. The structure of RuPhos will be of assistance in the use of this ligand in the design of cross-coupling catalysts.
PubMed: 33614148
DOI: 10.1107/S2056989021000542 -
Molecules (Basel, Switzerland) Sep 2022Conventional Staudinger reductions of organic azides are sluggish with aryl or bulky aliphatic azides. In addition, Staudinger reduction usually requires a large excess...
Conventional Staudinger reductions of organic azides are sluggish with aryl or bulky aliphatic azides. In addition, Staudinger reduction usually requires a large excess of water to promote the decomposition of the -ylide intermediate into phosphine oxide and amine products. To overcome the challenges above, we designed a novel triaryl phosphine reagent with an -SONH substituent. Herein, we report that such phosphine reagents are able to mediate the Staudinger reduction of both aryl and alkyl azides in either anhydrous or wet solvents. Good to excellent yields were obtained in all cases (even at a diluted concentration of 0.01 M). The formation of B-TAP, a cyclic -ylide, instead of phosphine oxide, eliminates the requirement of water in the Staudinger reduction. In addition, computational studies disclose that the intramolecular protonation of the -ylide by the -SONH group is kinetically favorable and responsible for the acceleration of Staudinger reduction of the aryl azides.
Topics: Amines; Azides; Indicators and Reagents; Oxides; Water
PubMed: 36080474
DOI: 10.3390/molecules27175707 -
Chemical Science Feb 2022Two new tris-heteroleptic Ru(ii) complexes with triphenylphosphine (PPh) coordination, -[Ru(phen)(PPh)(CHCN)] (1a, phen = 1,10-phenanthroline) and...
Two new tris-heteroleptic Ru(ii) complexes with triphenylphosphine (PPh) coordination, -[Ru(phen)(PPh)(CHCN)] (1a, phen = 1,10-phenanthroline) and -[Ru(biq)(phen)(PPh)(CHCN)] (2a, biq = 2,2'-biquinoline), were synthesized and characterized for photochemotherapeutic applications. Upon absorption of visible light, 1a exchanges a CHCN ligand for a solvent water molecule. Surprisingly, the steady-state irradiation of 2a followed by electronic absorption and NMR spectroscopies reveals the photosubstitution of the PPh ligand. Phosphine photoinduced ligand exchange with visible light from a Ru(ii) polypyridyl complex has not previously been reported, and calculations reveal that it results from a -type influence in the excited state. Complexes 1a and 2a are not toxic against the triple negative breast cancer cell line MDA-MB-231 in the dark, but upon irradiation with blue light, the activity of both complexes increases by factors of >4.2 and 5.8, respectively. Experiments with PPh alone show that the phototoxicity observed for 2a does not arise from the released phosphine ligand, indicating the role of the photochemically generated ruthenium aqua complex on the biological activity. These complexes represent a new design motif for the selective release of PPh and CHCN for use in photochemotherapy.
PubMed: 35308843
DOI: 10.1039/d1sc05647f -
ACS Pharmacology & Translational Science Dec 2022Phosphinic peptides constitute an important class of bioactive compounds that have found a wide range of applications in the field of biology and pharmacology of... (Review)
Review
Phosphinic peptides constitute an important class of bioactive compounds that have found a wide range of applications in the field of biology and pharmacology of Zn-metalloproteases, the largest family of proteases in humans. They are designed to mimic the structure of natural substrates during their proteolysis, thus acting as mechanism-based, transition state analogue inhibitors. A combination of electrostatic interactions between the phosphinic acid group and the Zn cation as well as optimal noncovalent enzyme-ligand interactions can result in both high binding affinity for the desired target and selectivity against other proteases. Due to these unique properties, phosphinic peptides have been mainly employed as tool compounds for (a) the purposes of rational drug design by serving as ligands in X-ray crystal structures of target enzymes and allowing the identification of crucial interactions that govern optimal molecular recognition, and (b) the delineation of biological pathways where Zn-metalloproteases are key regulators. For the latter objective, inhibitors of the phosphinopeptidic type have been used either unmodified or after being transformed to probes of various types, thus expanding the arsenal of functional tools available to researchers. The aim of this review is to summarize all recent research achievements in which phosphinic peptides have played a central role as tool compounds in the understanding of the mechanism and biological functions of Zn-metalloproteases in both health and disease.
PubMed: 36524013
DOI: 10.1021/acsptsci.2c00183 -
Inorganic Chemistry Aug 2022We report the isolation and characterization of a series of three cobalt(II) bis(phosphine) complexes with varying numbers of coordinated solvent ligands in the axial...
We report the isolation and characterization of a series of three cobalt(II) bis(phosphine) complexes with varying numbers of coordinated solvent ligands in the axial position. X-ray quality crystals of [Co(dppv)][BF] , [Co(dppv)(NCCH)][BPh] , and [Co(dppv)(NCCH)][BF] (dppv = -1,2-bis(diphenylphosphino)ethylene) were grown under slightly different conditions, and their structures were compared. This analysis revealed multiple crystallization motifs for divalent cobalt(II) complexes with the same set of phosphine ligands. Notably, the 4-coordinate complex is a rare example of a square-planar cobalt(II) complex, the first crystallographically characterized square-planar Co(II) complex containing only neutral, bidentate ligands. Characterization of the different axial geometries via EPR and UV-visible spectroscopies showed that there is a very shallow energy landscape for axial ligation. Ligand field angular overlap model calculations support this conclusion, and we provide a strategy for tuning other ligands to be axially labile on a phosphine scaffold. This methodology is proposed to be used for designing cobalt phosphine catalysts for a variety of oxidation and reduction reactions.
Topics: Cobalt; Crystallography, X-Ray; Ligands; Oxidation-Reduction; Phosphines
PubMed: 35920800
DOI: 10.1021/acs.inorgchem.2c01562