Investigation of the Effects and Mechanisms of Anticancer Action of a Ru(II)-Arene Iminophosphorane Compound in Triple Negative Breast Cancer Cells.

Triple negative breast cancer (TNBC) is one of the breast cancers with poorer prognosis and survival rates. TNBC has a disproportionally high incidence and mortality in women of African descent. We report on the evaluation of Ru-IM (1), a water-soluble organometallic ruthenium compound, in TNBC cell lines derived from patients of European (MDA-MB-231) and African (HCC-1806) ancestry (including IC50 values, cellular and organelle uptake, cell death pathways, cell cycle, effects on migration, invasion, and angiogenesis, a preliminary proteomic analysis, and an NCI 60 cell-line panel screen). 1 was previously found highly efficacious in MDA-MB-231 cells and xenografts, with little systemic toxicity and preferential accumulation in the tumor. We observe a similar profile for this compound in the two cell lines studied, which includes high cytotoxicity, apoptotic behavior and potential antimetastatic and antiangiogenic properties. Cytokine M-CSF, involved in the PI3/AKT pathway, shows protein expression inhibition with exposure to 1. We also demonstrate a p53 independent mechanism of action.

Phosphorene and Na-, Ca-, and Fe-doped phosphorene as candidates for delivery of mercaptopurine and fluorouracil anticancer drugs.

Phosphorene ability for delivery of mercaptopurine and fluorouracil was investigated by the density functional theory (DFT) method. However, the effects of Na, Ca, and Fe as dopants on phosphorene electronic properties such as HOMO and LUMO energies, density of states, chemical potential, electrophilicity index, softness, hardness, and its ability for drug delivery were studied. Natural bond orbital (NBO) analysis was performed. Our findings indicate that metallic dopants can improve the ability of phosphorene. Calcium-doped phosphorene has the greatest adsorption energy.

Cu(I) Complexes of Multidentate N,C,N- and P,C,P-Carbodiphosphorane Ligands and Their Photoluminescence.

A series of dinuclear copper(I) N,C,N- and P,C,P-carbodiphosphorane (CDP) complexes using multidentate ligands CDP(Py)2 (1) and (CDP(CH2PPh2)2 (13) have been isolated and characterized. Detailed structural information was gained by single-crystal XRD analyses of nine representative examples. The common structural motive is the central double ylidic carbon atom with its characteristic two lone pairs involved in the binding of two geminal L-Cu(I) fragments at Cu-Cu distances in the range 2.55-2.67 Å. In order to enhance conformational rigidity within the characteristic Cu-C-Cu triangle, two types of chelating side arms were symmetrically attached to each phosphorus atom: two 2-pyridyl functions in ligand CDP(Py)2 (1) and its dinuclear copper complexes 2-9 and 11, as well as two diphenylphosphinomethylene functions in ligand CDP(CH2PPh2)2 (13) and its di- and mononuclear complexes 14-18. Neutral complexes were typically obtained via the reaction of 1 with Cu(I) species CuCl, CuI, and CuSPh or via the salt elimination reaction of [(CuCl)2(CDP(Py)2] (2) with sodium carbazolate. Cationic Cu(I) complexes were prepared upon treating 1 with two equivalents of [Cu(NCMe)4]PF6, followed by the addition of either two equivalents of an aryl phosphine (PPh3, P(C6H4OMe)3) or one equivalent of bisphosphine ligands bis[(2-diphenylphosphino)phenyl] ether (DPEPhos), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos), or 1,1'-bis(diphenyl-phosphino) ferrocene (dppf). For the first time, carbodiphosphorane CDP(CH2PPh2)2 (13) could be isolated upon treating its precursor [CH(dppm)2]Cl (12) with NaNH2 in liquid NH3. A protonated and a deprotonated derivative of ligand 13 were prepared, and their coordination was compared to neutral CDP ligand 13. NMR analysis and DFT calculations reveal that the most stable tautomer of 13 does not show a CDP (or carbone) structure in its uncoordinated base form. For most of the prepared complexes, photoluminescence upon irradiation with UV light at room temperature was observed. Quantum yields (ΦPL) were determined to be 36% for dicationic [(CuPPh3)2(CDP(Py)2)](PF6)2 (4) and 60% for neutral [(CuSPh)2(CDP(CH2PPh2)2] (16).

One Reacts as Two: Applications of N-Isocyaniminotriphenylphosphorane in Diversity-Oriented Synthesis.

N-Isocyaniminotriphenylphosphorane (NIITP) is a functionalized isonitrile that has been extensively applied in a variety of organic reactions during the last two decades. This Review summarizes the most important applications in organic synthesis of this versatile reactant, with the focus posed on mechanistic and methodological aspects allowing the generation of molecular diversity. NIITP combines the reactivity of isonitriles with that of phosphoranes to enable chemical transformations employed in the construction of compound libraries. Here, we cover from the initial applications of NIITP in the Nef isocyanide reaction to further derivations that render a variety of heterocyclic scaffolds. The presence of the isonitrile moiety in this singular compound makes possible the double addition of nucleophiles and electrophiles, which followed by inter(intra)molecular aza-Wittig type transformations enable several multicomponent and tandem processes. In particular, we stress the impact of NIITP in oxadiazole chemistry, from the early two-component transformations to recent examples of multicomponent reactions that take place in the presence of suitable electrophiles. In addition, we briefly describe the role of NIITP chemistry in generating skeletal and conformational diversity in cyclic peptides. The reaction of NIITP with alkynes is thoroughly revised, with particular emphasis on silver-catalyzed processes that have been developed in the last years. Biomedicinal applications of some reaction products are also mentioned along with a perspective of future applications of this reactant.

Side-Chain Modification of Peptides Using a Phosphoranylidene Amino Acid.

The flexible variation of peptidomimetics is of great interest for the identification of optimized protein ligands. Here we present a general concept for introducing side-chain modifications into peptides using triarylphosphonium amino acids. Building blocks 4a and 4b are activated for amidation and incorporated into stable peptides. The obtained phosphoranylidene peptides undergo Wittig olefinations and 1,3-dipolar cycloaddition reactions, yielding peptidomimetics with vinyl ketones and 5-substituted 1,2,3-triazoles as non-native peptide side chains.

Characterization of Phosphoranes Obtained by the Spontaneous Carbonyl-Catalyzed Phosphorylation of Monosaccharides and Polyols in Aqueous Media.

Phosphorylation is a very important biochemical process in metabolism and biochemical marking. The mechanism for the biophosphorylation of substrates and the hydrolysis/transesterification of RNA has been suggested to proceed through phosphorane intermediates. Although the phosphorane intermediate/transition state has long been a subject of many theoretical models and studies, it has neither been isolated nor characterized, with most information derived from the hydrolysis and radiolabeling of cyclic phosphotriesters. We herein present the first report of the spontaneous phosphorylation of sugars and polyols in the absence of enzymes. That is, aldehydes and ketones combine with inorganic phosphates to form activated phosphates that phosphorylate alcohols without the requirement of any enzyme or additional activating agent. This phosphorylation is particularly favored in polyhydroxycarbonyls that can form internal cyclic acetals to give rise to the corresponding acetal phosphoranes. We have further characterized these phosphoranes and demonstrated their dehydration to the corresponding phosphates by using high-resolution mass spectroscopy. The phosphorylation of adenosine and uridine to form the corresponding phosphoranes was also achieved.

Binary Phosphorene Redox Behavior in Oxidoreductase Enzymatic Systems.

Phosphorene is a two-dimensional material that has many advantageous electronic, electrochemical, and optical properties. However, phosphorene possesses a relatively poor stability in ambient atmosphere. This disadvantage limits its application in several systems and particularly in electrochemical biosensors. Here we evaluate phosphorene as an electrochemical biosensing platform in two different mediator-based oxidoreductase enzymatic systems (glucose oxidase (GOx) and peroxidase from horseradish (HRP)), in which their detection is based on the reduction or oxidation of a mediator. In both cases, the used mediator is the same, ferrocene methanol (FcMeOH). Enhanced electrochemical activity is observed only in the reductive system (HRP-based biosensor) when compared to the oxidative counterpart (GOx-based biosensor). This phenomenon is attributed to the fact that in a reductive environment the phosphorene structure remains intact, while in an oxidative potential, the phosphorene is readily oxidized. In this way, the electroactivity of phosphorene as a sensing platform is strongly dependent on the type of mediator-based enzymatic system. These findings of binary nature of phosphorene are of high importance for construction of phosphorene-sensing platforms and in the development of enzyme logic systems.

Design, Isolation, and Spectroscopic Analysis of a Tetravalent Terbium Complex.

Synthetic strategies to yield molecular complexes of high-valent lanthanides, other than the ubiquitous Ce4+ ion, are exceptionally rare, and thorough, detailed characterization in these systems is limited by complex lifetime and reaction and isolation conditions. The synthesis of high-symmetry complexes in high purity with significant lifetimes in solution and the solid state is essential for determining the role of ligand-field splitting, multiconfigurational behavior, and covalency in governing the reactivity and physical properties of these potentially technologically transformative tetravalent ions. We report the synthesis and physical characterization of an S4 symmetric, four-coordinate tetravalent terbium complex, [Tb(NP(1,2-bis-tBu-diamidoethane)(NEt2))4] (where Et is ethyl and tBu is tert-butyl). The ligand field in this complex is weak and the metal-ligand bonds sufficiently covalent so that the tetravalent terbium ion is stable and accessible via a mild oxidant from the anionic, trivalent, terbium precursor, [(Et2O)K][Tb(NP(1,2-bis-tBu-diamidoethane)(NEt2))4]. The significant stability of the tetravalent complex enables its thorough characterization. The stepwise development of the supporting ligand points to key ligand control elements for further extending the known tetravalent lanthanide ions in molecular complexes. Magnetic susceptibility, electron paramagnetic resonance (EPR) spectroscopy, X-ray absorption near-edge spectroscopy (XANES), and density functional theory studies indicate a 4f7 ground state for [Tb(NP(1,2-bis-tBu-diamidoethane)(NEt2))4] with considerable zero-field splitting, demonstrating that magnetic, tetravalent lanthanide ions engage in covalent metal-ligand bonds. This result has significant implications for the use of tetravalent lanthanide ions in magnetic applications since the observed zero-field splitting is intermediate between that observed for the trivalent lanthanides and for the transition metals. The similarity of the multiconfigurational behavior in the ground state of [Tb(NP(1,2-bis-tBu-diamidoethane)(NEt2))4] (measured by Tb L3-edge XAS) to that observed in TbO2 implicates ligand control of multiconfigurational behavior as a key component of the stability of the complex.

Understanding structures and properties of phosphorene/perovskite heterojunction toward perovskite solar cell applications.

Two-dimensional black phosphorus (phosphorene) has drawn much attention in recent years due to its excellent electronic and optical properties. In this manuscript, we employ ab initio calculations to investigate the structural origin of the phosphorene/perovskite heterostructure. The calculations suggest that the chemical stability and the mechanical stability depend on the surface terminations, and the mechanical stability of the phosphorene/perovskite heterojunction should be further improved. The weak interactions between the P atoms in the phosphorene and the under-coordinated Pb atoms at the perovskite surfaces, as well as the weak interfacial charge transfer characters, are proposed to be mainly responsible for the moderate heterostructure stability. Suggestions to improve the stability of the heterojunction are provided. This study helps the fundamental understanding of the interaction between the phosphorene and the halide perovskite materials, and could provide a foundation for the better understanding of the low-dimensional materials in perovskite-based optoelectronic devices.

Reactive cyclic intermediates in the ProTide prodrugs activation: trapping the elusive pentavalent phosphorane.

Nucleotide prodrugs (ProTides) based on phosphate or phosphonate compounds are potent and successfully marketed antiviral drugs. Although their biological properties are well explored, experimental evidence on the mechanism of their activation pathway is still missing. In this study, we synthesized two ProTide analogues, which can be activated by UV light. Using 31P and 13C NMR spectroscopy with in situ irradiation, we followed the ProTide activation pathway in various solvents, and we detected the first proposed intermediate and the monoamidate product. Furthermore, we used mass spectrometry (MS) coupled with infrared spectroscopy in the gas phase to detect and to characterize the elusive cyclic pentavalent phosphorane and cyclic acyl phosphoramidate intermediates. Our combined NMR and MS data provided the first experimental evidence of the cyclic intermediates in the activation pathway of ProTide prodrugs.

Insertion of a Nontrigonal Phosphorus Ligand into a Transition Metal-Hydride: Direct Access to a Metallohydrophosphorane.

The synthesis and reactivity of an NPN-chelating ligand containing a nontrigonal phosphorous triamide center (L1 = P(N( o-N(2-pyridyl)C6H4)2) is reported. Metalation of L1 with RuCl2(PPh3)3 gives RuCl2(PPh3)(L1) (2). By contrast, metalation of L1 with RuHCl(CO)(PPh3)3 yields RuCl(CO)(PPh3)(L1H) (3), a chelated 10-P-5 ruthenahydridophosphorane, via net insertion into the Ru-H bond. Hydride abstraction from 3 with Ph3CPF6 gives [RuCl(CO)(PPh3)(L1)]PF6 (4); reaction of 4 with NaBH4 returns 3.

Adsorption behavior of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin on pristine and doped black phosphorene: A DFT study.

Polychlorinated dibenzo-p-dioxins (PCDDs) are highly toxic to humans. The search for novel and effective methods and materials for detecting or removing these gas pollutants is becoming more important and urgent. With its high specific surface area, abundance, and variety of potential applications, phosphorene has attracted much research interest. In this study, density functional theory was used to study the interactions between a doped phosphorene sheet and a tetrachlorodibenzo-p-dioxin (TCDD) molecule. The initial configurations of the TCDD and metallic (Ca or Ti) or nonmetallic (S and Se) dopants were investigated during the TCDD-phosphorene interaction study. Adsorption energy, isosurface of electron density difference, and density of states analysis were utilized to explore the interactions between TCDD and phosphorene. The results indicated that Ca dopant effectively improved the interaction between TCDD and phosphorene. Se dopant reduced the interaction between TCDD and phosphorene. Combining interactions between TCDD and the pristine, Ca-doped, and Se-doped phosphorenes, phosphorene could be a promising candidate for TCDD sensing and removal.

Chiral Hypervalent, Pentacoordinated Phosphoranes.

This review presents synthetic procedures applied to the preparation of chiral (mainly optically active) pentacoordinated, hypervalent mono and bicyclic phosphoranes. The mechanisms of their stereoisomerization and their selected interconversions are also presented.

Ravynic acid, an antibiotic polyeneyne tetramic acid from Penicillium sp. elucidated through synthesis.

A new antibiotic natural product, ravynic acid, has been isolated from a Penicillium sp. of fungus, collected from Ravensbourne National Park. The 3-acylpolyenyne tetramic acid structure was definitively elucidated via synthesis. Highlights of the synthetic method include the heat induced formation of the 3-acylphosphorane tetramic acid and a selective Wittig cross-coupling to efficiently prepare the natural compounds carbon skeleton. The natural compound was shown to inhibit the growth of Staphylococcus aureus down to concentrations of 2.5 µg mL(-1).

First paraben substituted cyclotetraphosphazene compounds and DNA interaction analysis with a new automated biosensor.

Cancer, as one of the leading causes of death in the world, is caused by malignant cell division and growth that depends on rapid DNA replication. To develop anti-cancer drugs this feature of cancer could be exploited by utilizing DNA-damaging molecules. To achieve this, the paraben substituted cyclotetraphosphazene compounds have been synthesized for the first time and their effect on DNA (genotoxicity) has been investigated. The conventional genotoxicity testing methods are laborious, take time and are expensive. Biosensor based assays provide an alternative to investigate this drug/compound DNA interactions. Here for the first time, a new, easy and rapid screening method has been used to investigate the DNA damage, which is based on an automated biosensor device that relies on the real-time electrochemical profiling (REP™) technology. Using both the biosensor based screening method and the in vitro biological assay, the compounds 9 and 11 (propyl and benzyl substituted cyclotetraphosphazene compounds, respectively), have resulted in higher DNA damage than the others with 65% and 80% activity reduction, respectively.

The specific functionalization of cyclotriphosphazene for the synthesis of smart dendrimers.

Hexachlorocyclotriphosphazene is an old compound which affords very new properties in the field of dendrimers. Indeed, it can be used as a branching point for the rapid synthesis of highly dense dendrimers, but also for the synthesis of dendrimers having precisely one function different from all the others. These types of dendrimers are useful in the field of materials, affording highly reusable catalysts, chemical sensors, or supports for cell cultures. However, the most developed uses concern fluorescence. These dendrimers have been used for in vivo imaging, and for trying to elucidate biological mechanisms, in particular for anti-inflammatory dendrimers. This review will display important examples in the field.

Cyclometalated Iminophosphorane Gold(III) and Platinum(II) Complexes. A Highly Permeable Cationic Platinum(II) Compound with Promising Anticancer Properties.

New organometallic gold(III) and platinum(II) complexes containing iminophosphorane ligands are described. Most of them are more cytotoxic to a number of human cancer cell lines than cisplatin. Cationic Pt(II) derivatives 4 and 5, which differ only in the anion, Hg2Cl6(2-) or PF6(-) respectively, display almost identical IC50 values in the sub-micromolar range (25-335-fold more active than cisplatin on these cell lines). The gold compounds induced mainly caspase-independent cell death, as previously reported for related cycloaurated compounds containing IM ligands. Cycloplatinated compounds 3, 4, and 5 can also activate alternative caspase-independent mechanisms of death. However, at short incubation times cell death seems to be mainly caspase dependent, suggesting that the main mechanism of cell death for these compounds is apoptosis. Mercury-free compound 5 does not interact with plasmid (pBR322) DNA or with calf thymus DNA. Permeability studies of 5 by two different assays, in vitro Caco-2 monolayers and a rat perfusion model, have revealed a high permeability profile for this compound (comparable to that of metoprolol or caffeine) and an estimated oral fraction absorbed of 100%, which potentially makes it a good candidate for oral administration.

Highly E-Selective and Enantioselective Michael Addition to Electron-Deficient Internal Alkynes Under Chiral Iminophosphorane Catalysis.

A highly E-selective and enantioselective conjugate addition of 2-benzyloxythiazol-5(4H)-ones to ß-substituted alkynyl N-acyl pyrazoles is achieved under the catalysis of a P-spiro chiral iminophosphorane. Simultaneous control of the newly generated central chirality and olefin geometry is possible with a wide array of the alkynyl Michael acceptors possessing different aromatic and aliphatic ß-substituents, as well as the various α-amino acid-derived thiazolone nucleophiles. This protocol provides access to structurally diverse, optically active α-amino acids bearing a geometrically defined trisubstituted olefinic component at the α-position.

Participation of an additional 4'-hydroxymethyl group in the cleavage and isomerization of ribonucleoside 3'-phosphodiesters.

4'-(Hydroxymethyl)uridylyl-3',5'-thymidine, an RNA model bearing an extra hydroxymethyl group at the 4'-position of the 3'-linked nucleoside, has been prepared and its cleavage and isomerization reactions studied over a wide pH range (from 0 to 12). Overall, the pH-rate profiles of these reactions were very similar to those of uridylyl-3',5'-uridine (UpU) - only a very modest acceleration was observed under acidic and neutral conditions. Evidently, hydrogen bond assistance by the additional hydroxymethyl function does not play a significant role.

Fluorescent and cross-linked organic-inorganic hybrid nanoshells for monitoring drug delivery.

Functionalized and monodisperse nanoshells have attracted significant attention owing to their well-defined structure, unique properties, and wide range of potential applications. Here, the synthesis of cross-linked organic-inorganic hybrid nanoshells with strong fluorescence properties was reported via a facile precipitation polymerization of hexachlorocyclotriphosphazene (HCCP) and fluorescein on silica particles used as templates. The resulting poly(cyclotriphosphazene-co-fluorescein) (PCTPF) nanoshells were firm cross-linked shells with ∼2.2 nm mesopores that facilitated the transport of drug molecules. The fluorescent nanoshells also exhibited excellent water dispersibility and biocompatibility; thus, they can be considered as ideal drug vehicles with high doxorubicin storage capacity (26.2 wt %) and excellent sustained release (up to 14 days). Compared to doxorubicin (DOX) alone, the PCTPF nanoshells more efficiently delivered DOX into and killed cancer cells. Moreover, the PCTPF nanoshells also exhibited remarkable fluorescent emission properties and improved photobleaching stability in both suspension and solid state owing to the covalent immobilization of fluorescein in the highly cross-linked organic-inorganic hybrids. The exceptional fluorescent properties enabled the release of DOX as well as the distribution of nanoshells and DOX to be monitored.