Porphyrinoid actinide complexes.

The diverse coordination modes and electronic features of actinide complexes of porphyrins and related oligopyrrolic systems (referred to as "porpyrinoids") have been the subject of interest since the 1960s. Given their stability and accessibility, most work with actinides has focused on thorium and uranium. This trend is also seen in the case of porphyrinoid-based complexation studies. Nevertheless, the diversity of ligand environments provided by porphyrinoids has led to the stabilization of a number of unique complexes with the early actinides that are often without structural parallel within the broader coordination chemical lexicon. This review summarizes key examples of prophyrinoid actinide complexes reported to date, including the limited number of porphyrinoid systems involving transuranic elements. The emphasis will be on synthesis and structure; however, the electronic features and reactivity pattern of representative systems will be detailed as well. Coverage is through December of 2021.

Applications of Low-Valent Transition Metalates: Development of a Reactive Noncarbonyl Rhenium(I) Anion.

Low-valent transition metalates─anionic, electronic-rich organometallic complexes─comprise a class of highly reactive chemical reagents that find integral applications in organic synthesis, small-molecule activation, transient species stabilization, and M-E bond formation, among others. The inherent reactivity of such electron-rich metal centers has necessitated the widespread use of strong backbonding ligands, particularly carbonyls, to aid in the isolation and handling of metalate reagents, albeit sometimes at the expense of partially masking their full reactivity. However, recent synthetic explorations into transition-metalate complexes devoid of archetypic back-bonding ligands have led to the discovery of highly reactive metalates capable of performing a variety of novel chemical transformations.Building on our group's long-standing interest in reactive organometallic species, a series of rational progressions in early-to-middle transition-metal chemistry ultimately led to our isolation of a rhenium(I) ß-diketiminate cyclopentadienide metalate that displays exceptional reactivity. We have found this Re(I) metalate to be capable of small-molecule activation; notably, the complex reversibly binds dinitrogen in solution and can be utilized to trap N2 for the synthesis of functionalized diazenido species. By employing isolobal analogues to N2 (CO and RNC), we were able to thoroughly monitor the mechanism of activation and conclude that the metalate's sodium counterion plays an integral role in promoting dinitrogen activation through a novel side-on interaction. The Re(I) metalate is also used in forming a variety of M-E bonds, including a series of uncommon rhenium-tetrylene (Si, Ge, and Sn) complexes that display varying degrees of multiple bonding. These metal tetrylenes act to highlight deviations in chemical properties within the group 14 elements. Our metalate's utility also applies to metal-metal bond formation, as demonstrated through the synthesis of a heterotetrametallic rhenium-zinc dimer. In this reaction, the Re(I) metalate performs a dual role as a reductant and metalloligand to stabilize a transient Zn22+ core fragment. Finally, the metalate displays unique reactivity with uranium(III) to yield the first transition metal-actinide inverse-sandwich bonds, in this case with three rhenium fragments bound through their Cp moieties surrounding the uranium center. Notably, throughout these endeavors we demonstrate that the metalate displays reactivity at multiple locations, including directly at the rhenium metal center, at a Cp carbon, through a Cp-sandwich mode, or through reversibly bound dinitrogen.Overall, the rhenium(I) metalate described herein demonstrates utility in diverse applications: small-molecule activation, the stabilization of reduced and/or unstable species, and the formation of unconventional M-E/M-M bonds or heterometallic complexes. Moving forward, we suggest that the continued discovery of noncarbonyl, electron-rich transition-metal anions featuring new or unconventional ligands should produce additional reactive organometallic species capable of stabilizing unique structural motifs and performing novel and unusual chemical transformations.

A Uranium(II) Arene Complex That Acts as a Uranium(I) Synthon.

Two-electron reduction of the amidate-supported U(III) mono(arene) complex U(TDA)3 (2) with KC8 yields the anionic bis(arene) complex [K[2.2.2]cryptand][U(TDA)2] (3) (TDA = N-(2,6-di-isopropylphenyl)pivalamido). EPR spectroscopy, magnetic susceptibility measurements, and calculations using DFT as well as multireference CASSCF methods all provide strong evidence that the electronic structure of 3 is best represented as a 5f4 U(II) metal center bound to a monoreduced arene ligand. Reactivity studies show 3 reacts as a U(I) synthon by behaving as a two-electron reductant toward I2 to form the dinuclear U(III)-U(III) triiodide species [K[2.2.2]cryptand][(UI(TDA)2)2(µ-I)] (6) and as a three-electron reductant toward cycloheptatriene (CHT) to form the U(IV) complex [K[2.2.2]cryptand][U(η7-C7H7)(TDA)2(THF)] (7). The reaction of 3 with cyclooctatetraene (COT) generates a mixture of the U(III) anion [K[2.2.2]cryptand][U(TDA)4] (1-crypt) and U(COT)2, while the addition of COT to complex 2 instead yields the dinuclear U(IV)-U(IV) inverse sandwich complex [U(TDA)3]2(µ-η8:η3-C8H8) (8). Two-electron reduction of the homoleptic Th(IV) amidate complex Th(TDA)4 (4) with KC8 gives the mono(arene) complex [K[2.2.2]cryptand][Th(TDA)3(THF)] (5). The C-C bond lengths and torsion angles in the bound arene of 5 suggest a direduced arene bound to a Th(IV) metal center; this conclusion is supported by DFT calculations.

Frequency of Dosing of Cephalexin for Oral Step-Down Therapy of Pediatric Osteoarticular Infections Caused by Methicillin-Sensitive Staphylococcus Aureus.

Osteoarticular infections are one of the more common invasive bacterial infections encountered in children. There exist significant practice variations in both the diagnosis and treatment of such infections. However, the practice of transitioning from parenteral therapy to oral antibiotics has been well validated by several studies. For methicillin-sensitive Staphylococcus aureus (MSSA), cephalexin is often recommended. Prospective, controlled data regarding optimal dosing of cephalexin in pediatric osteomyelitis are not available. We sought to review our retrospective, uncontrolled data on four times daily (QID) versus three times daily (TID) dosing of cephalexin for pediatric osteoarticular infections. Children ≥1 month to <18 years of age admitted to Rady Children's Hospital-San Diego with a diagnosis of osteomyelitis or septic arthritis between January 1, 2002, and November 30, 2007, were identified and previously reported. Only patients with culture-positive MSSA infections are included in this report. Demographic and clinical data were manually extracted from the electronic medical record. Fifty-nine patients were treated with cephalexin and had records available for review through our electronic medical record. Thirty-eight patients (64.4%) were treated QID, and 21 patients (35.6%) were treated TID. Clinical cure was achieved in all patients with only one adverse event occurring in the QID group. In this retrospective chart review of children with osteoarticular infections caused by MSSA treated with cephalexin, similar clinical outcomes were found with QID versus TID dosing.

A Uranium Tri-Rhenium Triple Inverse Sandwich Compound.

Salt metathesis between the anionic rhenium(I) compound, Na[Re(η5-Cp)(BDI)] (BDI = N, N'-bis(2,6-diisopropylphenyl)-3,5-dimethyl-ß-diketiminate), and the uranium(III) salt, UI3(1,4-dioxane)1.5, generated the triple inverse sandwich complex, U[(µ-η5:η5-Cp)Re(BDI)]3, which was isolated and structurally characterized as the Lewis base adducts, (L)U[(µ-η5:η5-Cp)Re(BDI)]3 (1·L, L = THF, 1,4-dioxane, DMAP). The assignment as one uranium(III) and three rhenium(I) centers was supported by X-ray crystallography, NMR and EPR spectroscopies, and computational studies. An unusual shortening of the rhenium-Cp bond distances in 1·L relative to Na[Re(η5-Cp)(BDI)] was observed in the solid-state and reproduced in calculated structures of 1·THF and the anionic fragment, [Re(η5-Cp)(BDI)]-. Calculations suggest that the electropositive uranium center pulls electron density away from the electron-rich rhenium centers, reducing electron-electron repulsions in the rhenium-Cp moieties and thereby strengthening those interactions, while also making uranium-Cp bonding more favorable.

Origin of the unusually strong and selective binding of vanadium by polyamidoximes in seawater.

Amidoxime-functionalized polymeric adsorbents are the current state-of-the-art materials for collecting uranium (U) from seawater. However, marine tests show that vanadium (V) is preferentially extracted over U and many other cations. Herein, we report a complementary and comprehensive investigation integrating ab initio simulations with thermochemical titrations and XAFS spectroscopy to understand the unusually strong and selective binding of V by polyamidoximes. While the open-chain amidoxime functionalities do not bind V, the cyclic imide-dioxime group of the adsorbent forms a peculiar non-oxido V5+ complex, exhibiting the highest stability constant value ever observed for the V5+ species. XAFS analysis of adsorbents following deployment in environmental seawater confirms V binding solely by the imide-dioximes. Our fundamental findings offer not only guidance for future optimization of selectivity in amidoxime-based sorbent materials, but may also afford insight to understanding the extensive accumulation of V in some marine organisms.

Coffee inhibition of CYP3A4 in vitro was not translated to a grapefruit-like pharmacokinetic interaction clinically.

Grapefruit can augment oral medication bioavailability through irreversible (mechanism-based) inhibition of intestinal CYP3A4. Supplementary data from our recent coffee-drug interaction clinical study showed some subjects had higher area under the plasma drug concentration - time curve (AUC) and plasma peak drug concentration (Cmax) of the CYP3A4 probe felodipine compared to aqueous control. It was hypothesized that coffee might interact like grapefruit in responsive individuals. Beans from six geographical locations were consistently brewed into coffee that was separated chromatographically to a methanolic fraction for in vitro inhibition testing of CYP3A4 metabolism of felodipine at 1% coffee strength. The effect of simultaneous incubation and 10-min preincubation with coffee fractions determined whether coffee had direct and mechanism-based inhibitory activity. A subsequent five-way randomized balanced controlled crossover clinical study evaluated the clinical pharmacokinetic interaction with single-dose felodipine. Grapefruit juice, water, or three of the in vitro tested coffees were ingested at 300 mL alone 1 h before and then with felodipine. In vitro, all six coffees decreased felodipine metabolism for both simultaneous and preincubation exposure compared to corresponding control. Five coffees demonstrated mechanism-based inhibition. Grapefruit increased felodipine AUC0-8 (25 vs. 13 ng.h/mL, P < 0.001) and Cmax (5.8 vs. 2.7 ng/mL, P < 0.001) and decreased dehydrofelodipine/felodipine AUC0-8 ratio (0.84 vs. 1.29, P < 0.001), while the three coffees caused no change in these parameters compared to water. Despite high in vitro potency of CYP3A4 inhibition, the coffees did not cause a clinical pharmacokinetic interaction possibly from insufficient amount of inhibitor(s) in coffee reaching intestinal CYP3A4 during the absorption phase of felodipine. The results of this study highlight the need for follow-up clinical testing when in vitro results indicate the possibility of an interaction.

Coffee-Antihypertensive Drug Interaction: A Hemodynamic and Pharmacokinetic Study With Felodipine.

OBJECTIVES: A period of abstinence from coffee to permit caffeine elimination appears to enable increased blood pressure on subsequent exposure. We hypothesized that this would offset the antihypertensive effect of the dihydropyridine calcium channel blocker felodipine. METHODS: A randomized, single-dose, crossover study assessed hemodynamic and pharmacokinetic effects following 2 days without coffee and caffeine-containing foods. Consistently brewed black coffee (2×300ml), felodipine maximum recommended dose (10mg), and coffee plus felodipine were tested in middle-aged normotensive subjects. RESULTS: Pretreatment plasma caffeine concentrations were unquantifiable. After coffee, blood pressure changes (mm Hg) averaged over study hours 1-4 were increased for brachial systolic (7.6, P < 0.001) and diastolic (4.9, P < 0.001) and aortic systolic (7.4, P < 0.001), pulse (3.0, P < 0.05) and augmentation (1.4, P < 0.05) relative to baseline. After coffee plus felodipine, they were higher for brachial systolic (4.0, P < 0.05) and diastolic (3.9, P < 0.001) and aortic systolic (4.6, P < 0.05) compared to felodipine alone. The pressor effects of coffee and its modulation by felodipine were variable among individuals. Coffee containing caffeine (127mg) caused maximum pressor effect. Caffeine and felodipine pharmacokinetics were similar for coffee and felodipine given alone or in combination indicating an interaction having a pharmacodynamic basis. Plasma felodipine concentration-diastolic blood pressure reduction relationship shifted with coffee such that doubling the felodipine concentration would eliminate the pressor effect. However, this may increase the risk of adverse drug events particularly during the timeframe without coffee. CONCLUSION: Intermittent coffee ingestion might complicate hypertension diagnosis and management for many individuals.

Activation of white phosphorus by low-valent group 5 complexes: formation and reactivity of cyclo-P4 inverted sandwich compounds.

We report the synthesis and comprehensive study of the electronic structure of a unique series of dinuclear group 5 cyclo-tetraphosphide inverted sandwich complexes. White phosphorus (P4) reacts with niobium(III) and tantalum(III) ß-diketiminate (BDI) tert-butylimido complexes to produce the bridging cyclo-P4 phosphide species {[(BDI)(N(t)Bu)M]2(µ-η(3):η(3)P4)} (1, M = Nb; 2, M = Ta) in fair yields. 1 is alternatively synthesized upon hydrogenolysis of (BDI)Nb(N(t)Bu)Me2 in the presence of P4. The trinuclear side product {[(BDI)NbN(t)Bu]3(µ-P12)} (3) is also identified. Protonation of 1 with [HOEt2][B(C6F5)4] does not occur at the phosphide ring but rather involves the BDI ligand to yield {[(BDI(#))Nb(N(t)Bu)]2(µ-η(3):η(3)P4)}[B(C6F5)4]2 (4). The monocation and dication analogues {[(BDI)(N(t)Bu)Nb]2(µ-η(3):η(3)P4)}{B(Ar(F))4}n (5, n = 1; 6, n = 2) are both synthesized by oxidation of 1 with AgBAr(F). DFT calculations were used in combination with EPR and UV-visible spectroscopies to probe the nature of the metal-phosphorus bonding.

Effect of formulation pH on transdermal penetration of antiemetics formulated in poloxamer lecithin organogel.

The purpose of this study was to assess the impact of altering formulation pH on the transdermal penetration of several commonly used antiemetic, weakly basic drugs incorporated into poloxamer lecithin organogel vehicle. Poloxamer lecithin organogel formulations containing promethazine hydrochloride (25 mg/mL), metoclopramide hydrochloride (10 mg/mL), and ondansetron hydrochloride (8 mg/mL) were examined for both drug release and transdermal penetration across porcine skin in modified Franz diffusion cells for a period of 24 hours. For the transdermal studies, each antiemetic drug was formulated at a pH above and below their acid dissociation constant (pKa) in an attempt to assure that the drug would be primarily in their respective ionized or non-ionized states. In addition, drug content in skin was assessed at the end of the 24-hour experiment. Drug content analysis was determined via high-performance liquid chromatography. As a percent of total drug release from the poloxamer lecithin organogel vehicle, promethazine hydrochloride demonstrated the most transdermal drug penetration after 24 hours (30.2% +/- 20.2%), followed by ondansetron hydrochloride (2.7% +/- 1.1%) and metoclopramide hydrochloride (1.8% +/- 1.6%). Subsequently, the pH of the Pluronic F-127 gel was adjusted in order to ensure that each antiemetic drug would be primarily in its unionized state. The transdermal permeation of each antiemetic drug primarily in its unionized state increased over that observed with the drug primarily in its ionized state after 24 hours (promethazine: 1.6-fold increase; metoclopramide: 1.3-fold increase; ondansetron: 1.8-fold increase). A similar trend was noted in the amount of each drug found in the skin after 24 hours (promethazine: 1.2-fold increase; metoclopramide: 2.4-fold increase; ondansetron: 3.0-fold increase). These results suggest that proper optimization of drug ionization state may be a useful strategy for compounding pharmacists to increase the efficacy of drugs intended for inclusion in transdermal formulations.

West Nile virus encephalitis with thalamic involvement in an immunocompromised child.

West Nile virus has been an increasingly important pathogen in the United States since it was first reported in 1999. Neuroinvasive West Nile virus has been infrequently reported in the pediatric population. We report a case of severe West Nile virus encephalitis with cranial magnetic resonance imaging findings not yet described in children.

Tetradecylmaltoside (TDM) enhances in vitro and in vivo intestinal absorption of enoxaparin, a low molecular weight heparin.

Tetradecylmaltoside (TDM) was evaluated as a potential gastrointestinal absorption enhancer for low molecular weight heparin (LMWH), enoxaparin. The in vitro efficacy of TDM (0.0625, 0.125 and 0.25% w/v) in enhancing transport of 3H-enoxaparin or 14C-mannitol was investigated in human colonic epithelial cells (C2BBel). Metabolic stability of the drug was determined in C2BBel cell extracts. Transepithelial electrical resistance (TEER) was measured before and after exposure of the cells to TDM. Enoxaparin was further administered to anesthetized Sprague-Dawley rats in oral formulations in the absence or presence of increasing concentrations of TDM and drug absorption was monitored by measuring anti-factor Xa activity in rat blood. In vitro permeability study shows that apparent permeability (Papp) of 3H-enoxaparin across C2BBe1 cells was increased by 8-fold in the presence of 0.0625% TDM compared to untreated cells. The movement of 14C-mannitol across the cell monolayer followed a similar pattern in the presence of increasing concentrations of TDM. No degradation or depolymerization of enoxaparin was observed when the drug was incubated in C2BBel cell extract. TEER was reversible after 60 min exposure of the cells to 0.0625% (w/v) TDM. Oral formulations of enoxaparin containing TDM administered to anesthetized rats significantly and rapidly increased gastrointestinal absorption as compared to those animals which received enoxaparin plus saline (p < 0.05). In the presence of 0.125% TDM in the formulation, enoxaparin oral bioavailability was increased by 2.5-fold compared to the saline control group. Overall, the data on the effect of TDM on the in vitro and in vivo intestinal permeation of enoxaparin suggest that TDM may represent a promising excipient for use in oral LMWH formulations.