Chiral tridentate bis(oxazol-2-ylimino) isoindoline-based pincer ligands: isolation and characterization via deligation from in situ prepared Cd-ligand complexes.

The first isolation and structural characterization of a series of chiral trinitrogen 1,3-bis(4,5-dihydrooxazol-2-ylimino)isoindoline-based pincer ligands are reported. Cadmium complexes, isolated as Cd(L2X)2 where L2X is the deprotonated form of L2XH = 1,3-bis(4,5-dihydro-4-(R)-phenyloxazol-2-ylimino)-isoindoline ((R,R)-5H) or 1,3-bis(4,5-dihydro-4-(S)-iso-propyloxazol-2-ylimino)isoindoline ((S,S)-6H) were prepared in situ via traditional or microwave-based techniques with the latter being more efficient but less able to be scaled up at this time. Ligands (R,R)-5H and (S,S)-6H were isolated via deligation from their respective cadmium complexes using a thiol-based ligand exchange protocol. The characterization of ligands and their respective cadmium complexes, in both the solid (X-ray crystallography) and solution (NMR spectroscopy) states are reported. Pd((S,S)-6)(OAc) is reported as a proof-of-concept of the ability to prepare 1 : 1 ligand to metal ratio complexes that are believed to be necessary as potential enantioselective catalysts.

Accessing Ambiphilic Phosphine Boronates through C-H Borylation by an Unforeseen Cationic Iridium Complex.

Ambiphilic molecules, which contain a Lewis base and Lewis acid, are of great interest based on their unique ability to activate small molecules. Phosphine boronates are one class of these substrates that have interesting catalytic activity. Direct access to these phosphine boronates is described through the iridium-catalyzed C-H borylation of phosphines. An unconventional cationic iridium catalyst was identified as optimal for a range of phosphines, providing good yields and selectivity across a diverse class of phosphine boronates (isolated as the borane-protected phosphine). A complimentary catalyst system (quinoline-based silane ligand with [(COD)IrOMe]2 ) was optimal for biphenyl-based phosphines. Selective polyborylation was also shown providing bis- and tris-borylated phosphines. Deprotection of the phosphine boronate provided free ambiphilic phosphine boronates, which do not have detectable interactions between the phosphorus and boron atoms in solution or the solid state.

Benzoxazolinone aryl sulfonamides as potent, selective Nav1.7 inhibitors with in vivo efficacy in a preclinical pain model.

Studies on human genetics have suggested that inhibitors of the Nav1.7 voltage-gated sodium channel hold considerable promise as therapies for the treatment of chronic pain syndromes. Herein, we report novel, peripherally-restricted benzoxazolinone aryl sulfonamides as potent Nav1.7 inhibitors with excellent selectivity against the Nav1.5 isoform, which is expressed in the heart muscle. Elaboration of initial lead compound 3d afforded exemplar 13, which featured attractive physicochemical properties, outstanding lipophilic ligand efficiency and pharmacological selectivity against Nav1.5 exceeding 1000-fold. Key structure-activity relationships associated with oral bioavailability were leveraged to discover compound 17, which exhibited a comparable potency/selectivity profile as well as full efficacy following oral administration in a preclinical model indicative of antinociceptive behavior.

Thiocyanate-Ligated Heterobimetallic {PtM} Lantern Complexes Including a Ferromagnetically Coupled 1D Coordination Polymer.

A series of heterobimetallic lantern complexes with the central unit {PtM(SAc)4(NCS)} have been prepared and thoroughly characterized. The {Na(15C5)}[PtM(SAc)4(NCS)] series, 1 (Co), 2 (Ni), 3 (Zn), are discrete compounds in the solid state, whereas the {Na(12C4)2)}[PtM(SAc)4(NCS)] series, 4 (Co), 5 (Ni), 6 (Zn), and 7 (Mn), are ion-separated species. Compound 7 is the first {PtMn} lantern of any bridging ligand (carboxylate, amide, etc.). Monomeric 1-7 have M(2+), necessitating counter cations that have been prepared as {(15C5)Na}(+) and {(12C4)2Na}(+) variants, none of which form extended structures. In contrast, neutral [PtCr(tba)4(NCS)]∞ 8 forms a coordination polymer of {PtCr}(+) units linked by (NCS)(-) in a zigzag chain. All eight compounds have been thoroughly characterized and analyzed in comparison to a previously reported family of compounds. Crystal structures are presented for compounds 1-6 and 8, and solution magnetic susceptibility measurements are presented for compounds 1, 2, 4, 5, and 7. Further structural analysis of dimerized {PtM} units reinforces the empirical observation that greater charge density along the Pt-M vector leads to more Pt···Pt interactions in the solid state. Four structural classes, one new, of {MPt}···{PtM} units are presented. Solid state magnetic characterization of 8 reveals a ferromagnetic interaction in the {PtCr(NCS)} chain between the Cr centers of J/kB = 1.7(4) K.

Increases in intravenous magnesium use among hospitalized patients: an institution cross-sectional experience.

BACKGROUND: Among hospitalized patients, indications for the measurement of magnesium levels and treatment of hypomagnesemia with intravenous magnesium are not well defined. Recently, there have been reports of worldwide shortages of intravenous magnesium sulphate. OBJECTIVE: To examine secular trends in the administration of intravenous magnesium on hospital wards at a tertiary care institution. The secondary objective is to identify factors associated with magnesium use among admitted patients. METHODS: Retrospective cross-section review of hospitalized patients at a single Canadian tertiary care center. Utilization of non-parental nutrition intravenous magnesium from 2003 to 2013 stratified by hospital ward was examined. In addition, patient level data from select wards (including medical and surgical services) was examined at early and more recent time period (4/2006 versus 4/2013). RESULTS: Among the 248,329 hospitalized patients, intravenous magnesium use increased by 2.86 fold from 2003 to 2013. Not all wards had an increase whereas some had nearly a 10 fold increase in use. In the sample (n = 769), (adjusting for admission magnesium level, presence of an indication for intravenous magnesium, ward location, comorbidity and demographics) intravenous magnesium administration was higher (25.8 % versus 5.5 %) in 2013 versus 2006 (OR 13.91 (95 % CI, 6.21-31.17, p < 0.001). Despite this increase in intravenous magnesium administration, <3 % of patients were admitted on oral magnesium in 2006 and 2013. For patients receiving intravenous magnesium only a minority were discharged on oral therapy despite low levels. CONCLUSIONS: This center has witnessed a considerable increase in the use of in-hospital intravenous magnesium over the last 6 years that cannot be explained for by medical indications. The risks and benefits of this therapy deserve further study. If this change in practice is representative of other North American hospitals, it may be responsible for recent drug shortages.

CONTEXTE: Les indications concernant la mesure des niveaux sanguins de magnésium et le traitement de l'hypomagnésémie par infusion intraveineuse de magnésium chez les patients hospitalisés sont mal définies. On a récemment rapporté des pénuries à l'échelle mondiale de sulfate de magnésium destiné à l'infusion intraveineuse. OBJECTIFS: D'une part, examiner les tendances séculaires en matière d'administration de magnésium par voie intraveineuse dans divers services hospitaliers d'un centre de soins tertiaires. D'autre part, déterminer les facteurs associés à l'utilisation du magnésium chez les patients hospitalisés. MÉTHODES: Étude transversale et rétrospective auprès des patients hospitalisés dans un seul centre canadien de soins tertiaire. On a étudié un échantillon qui témoigne du recours à l'administration intraveineuse de magnésium, de 2003 à 2013, en stratifiant par service hospitalier. RÉSULTATS: Chez les 248 329 patients hospitalisés, le recours à l'infusion de magnésium par voie intraveineuse a augmenté de 2,86 fois entre 2003 et 2013. Dans certains services, aucune augmentation n'a été notée alors que dans d'autres, l'utilisation a augmenté de près de 10 fois. Dans l'échantillon (n = 769), (ajusté selon le taux de magnésium administré, la présence d'une indication nécessitant une infusion de magnésium, l'emplacement des services, la comorbidité et les données démographiques), l'administration de magnésium par voie intraveineuse était plus fréquente (25,8 % par rapport à 5,5 %) en 2013 qu'en 2006 (RIA = 13,91 (IC, 95 %, 6,21-31,17, p < 0,001). Malgré cette augmentation de l'utilisation du magnésium par voie intraveineuse, <3 % des patients avaient été admis pour administration orale de magnésium en 2006 et en 2013. Parmi les patients qui ne recevaient le magnésium que par voie intraveineuse, seule une minorité avait reçu son congé avec une thérapie par voie orale, en dépit des faibles taux. CONCLUSION: Nous avons observé une augmentation considérable dans l'utilisation de l'infusion de magnésium par voie intraveineuse en milieu hospitalier au cours des 6 dernières années, ce qui n'est pas justifié par des indications d'ordre médical. Les avantages et les risques que comporte cette thérapie méritent une étude approfondie. Ce changement de pratique, s'il s'observe dans d'autres hôpitaux nord-américains, pourrait expliquer les récentes pénuries de médicaments.

Synthesis of a phosphapyracene via metal-mediated cyclization: structural and reactivity effects of acenaphthene precursors.

Metal-mediated synthesis of a new heterocycle, 1-phenyl-phosphapyracene (Ph-4, Ph-PyraPhos), by tandem phosphination/cyclization of peri-substituted 5-bromo-6-chloromethylacenaphthene (3) was investigated for comparison to Pt-catalyzed formation of 1-phosphaacenaphthenes (2, AcePhos) from the analogous naphthalene precursor (1). Reaction of PH2Ph with , NaOSiMe3 and a Cu catalyst gave ; a Pt catalyst yielded PHPh(CH2Ar) (Ph-11, Ar = 5-Br-acenaphthyl). Deprotonation of a complex of this secondary phosphine, [Pt((R,R)-Me-DuPhos)(Ph)(PHPh(CH2Ar))][PF6] (17), generated the phosphido intermediate Pt((R,R)-Me-DuPhos)(Ph)(PPhCH2Ar) (Ph-8), which cyclized to give [Pt((R,R)-Me-DuPhos)(Ph)(Ph-PyraPhos)][PF6] (18). Treatment of P-8 with silver triflate gave 18 and the cyclometalated phosphine complex [Pt((R,R)-Me-DuPhos)(κ(2)-(P,C)-5-Ph2PCH2-6-C12H8)][PF6] (21), which might form via Pt(iv) intermediates. The effects of the added "ace" bridge on structure and reactivity are discussed.

Phosphine-directed C-H borylation reactions: facile and selective access to ambiphilic phosphine boronate esters.

Ambiphilic ligands have received considerable attention over the last two decades due to their unique reactivity as organocatalysts and ligands. The iridium-catalyzed C-H borylation of phosphines is described in which the phosphine is used as a directing group to provide selective formation of arylboronate esters with unique scaffolds of ambiphilic compounds. A variety of aryl and benzylic phosphines were subjected to the reaction conditions, selectively providing stable, isolable boronate esters upon protection of the phosphine as the borane complex. After purification, the phosphine-substituted boronate esters could be deprotected and isolated in pure form.

Generic immunosuppression in solid organ transplantation: a Canadian perspective.

The introduction of generic immunosuppressant medications may present an opportunity for cost savings in solid organ transplantation if equivalent clinical outcomes to the branded counterparts can be achieved. An interprofessional working group of the Canadian Society of Transplantation was established to develop recommendations on the use of generic immunosuppression in solid organ transplant recipients (SOTR) based on a review of the available data. Under current Health Canada licensing requirements, a demonstration of bioequivalence with the branded formulation in healthy volunteers allows for bridging of clinical data. Cyclosporine, tacrolimus, and sirolimus are designated as "critical dose drugs" and are held to stricter criteria. However, whether this provides sufficient guarantee of therapeutic equivalence in SOTR remains controversial, and failure to maintain an appropriate balance of immunosuppression may have serious consequences, including rejection, graft loss, and death. Published evidence supporting therapeutic equivalence of generic formulations in SOTR is lacking. Moreover, in the setting of multiple generic formulations the potential for uncontrolled product switching is a major concern, since generic preparations are not required to demonstrate bioequivalence with each other. Although close monitoring is recommended with any change in formulation, drug product switches are likely to occur without prescriber knowledge and may pose a significant patient safety risk. The advent of generic immunosuppression will require new practices including more frequent therapeutic drug and clinical monitoring, and increased patient education. The additional workload placed on transplant centers without additional funding will create challenges and could ultimately jeopardize patient outcomes. Until more robust clinical data are available and adequate regulatory safeguards are instituted, caution in the use of generic immunosuppressive drugs in solid organ transplantation is warranted.

Synthesis and characterization of an unsymmetrical cobalt(III) active site analogue of nitrile hydratase.

The design, synthesis, and characterization of an unsymmetrical diamidato-dithiol ligand (H(4) 1, where the hydrogen atoms represent deprotonatable amide and thiol protons) and its cobalt(III) complex, a synthetic analogue of the cobalt-containing nitrile hydratase enzyme family, are reported. The ligand was prepared in 24% yield from an overall eight-step synthetic pathway following a modified protocol established in our laboratory that includes two peptide couples using O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate as the coupling agent. The ligand and all precursors were characterized by NMR spectroscopy and elemental analysis. The cobalt nitrile hydratase synthetic analogue complex [NBu(4)][Co(1)] was prepared on deprotonating ligand H(4) 1 to [1](4-) on addition of 5 equiv of NaH in N,N-dimethylformamide and adding 1 equiv of CoCl(2) at -40 °C under a N(2) atmosphere followed by oxidizing the complex by stirring it overnight open to dry air. The complex [NBu(4)][Co(1)] was isolated after counterion exchange with 1 equiv of NBu(4)Cl followed by crystallization from MeCN/Et(2)O in 71% yield. The structure of the complex was confirmed by X-ray diffraction analysis. Cyclic voltammetry studies on [NBu(4)][Co(1)] in a 0.1 M [NBu(4)][PF(6)]/MeCN solution showed a quasi-reversible reduction potential at -1.1 V (vs. Ag/AgCl), and magnetic susceptibility investigations indicated the complex is paramagnetic in both the solid and the solution states as determined from inverse-Gouy and Evans NMR methods, respectively.

Novel metal complexes containing a chiral trinitrogen isoindoline-based pincer ligand: in situ synthesis and structural characterization.

The first synthesis and characterization of metal coordinated complexes containing in situ prepared chiral trinitrogen 1,3-bis(4,5-dihydrooxazol-2-ylimino)isoindoline-based pincer ligands are reported. Two zinc complexes, isolated as Zn(L)(2), where L = 1,3-bis(4,5-dihydro-4-(R)-phenyloxazol-2-ylimino)isoindoline ((R,R)-5) or 1,3-bis(4,5-dihydro-4-(S)-iso-propyloxazol-2-ylimino)isoindoline ((S,S)-6), respectively, are reported. Complexes Zn((R,R)-5)(2) and Zn((S,S)-6)(2) were prepared in situ through the condensation of phthalonitrile with enantiopure 2-amino-4-(R)-phenyloxazoline ((R)-3) or 2-amino-4-(S)-iso-propyloxazoline ((S)-4) in the presence of ZnCl(2) at 80 °C in dry toluene over 3-4 days. The characterizations of Zn((R,R)-5)(2) and Zn((S,S)-6)(2) in both the solid (X-ray crystallography) and solution (multinuclear NMR spectroscopy) states are reported.

Carbon-yl[tris-(3,5-diphenyl-pyrazol-1-yl-κN)methane]copper(I) hexa-fluorido-phosphate-dichloro-methane-diethyl ether (4/3/1).

In the title compound, [Cu(C(46)H(34)N(6))(CO)]PF(6)·0.75CH(2)Cl(2)·0.25C(4)H(10)O, the Cu(I) atom is coordinated by three N atoms from the tridentate chelating tris-(3,5-diphenyl-pyrazol-1-yl)methane ligand (average Cu-N distance = 2.055 Å) and the C atom from a carbon monoxide ligand in a distorted tetra-hedral coordination geometry. The average N-Cu-N angle between adjacent pyrazole-ring-coordinated N atoms is 88.6°, while the average N-Cu-C angle between the pyrazole-bound N atom and the C atom of carbon monoxide is 126.3°. One of the 3-phenyl rings of the tris-(pyrazol-yl)methane ligand is disordered over two sites each with an occupancy factor of 0.50. The structure also exhibits disorder of the monosolvate that has been modeled with 0.75 CH(2)Cl(2) and 0.25 Et(2)O occupancy.

catena-Poly[[[bis-(N,N-dimethyl-formamide)iron(II)]-{µ-2,2'-bis-(diphenyl-phosphino-yl)-N,N'-[(1R,2R)-cyclo-hexane-1,2-di-yl]dibenzamide}] bis-(perchlorate) N,N-dimethyl-formamide disolvate].

The title extended solid coordination compound, {[Fe(C(44)H(40)N(2)O(4)P(2))(C(3)H(7)NO)(2)](ClO(4))(2)·2C(3)H(7)NO}(n), was crystallized un-ex-pectedly from the reaction mixture containing the Trost ligand (1R,2R)-(+)-1,2-diamino-cyclo-hexane-N,N'-bis-(2'-di-phenyl-phosphinobenzo-yl) and Fe(ClO(4))(2)·6H(2)O in a 1:1 ratio in dimethyl-formamide (DMF) under reflux conditions. The polymeric complex is characterized by Fe(II) metal centers that are coordinated by two oxidized Trost ligands, each coordinated in a bidentate fashion in a square plane, along with two DMF mol-ecules above and below the plane [average Fe-O(DMF) = 2.086 (4) Å], forming an overall pseudo-octa-hedral geometry. The Trost ligand binds adjacent Fe(II) centers, each Fe(II) being bound through the O atom of one of the phosphine oxides [average Fe-O(PPh2) = 2.115 (4) Å] and the carbonyl O atom of the adjacent amide [average Fe-O(amide) = 2.192 (3) Å]. Disorder is observed in the co-solvated solvent: there are two DMF mol-ecules per Fe(II) centre, which were modeled as one DMF mol-ecule with complete occupancy and the other being modeled in two positions with equal occupancy. Disorder was also observed with one of the perchlorate anions, which was modeled in two positions with 0.75:0.25 occupancy.

YZGD from Paenibacillus thiaminolyticus, a pyridoxal phosphatase of the HAD (haloacid dehalogenase) superfamily and a versatile member of the Nudix (nucleoside diphosphate x) hydrolase superfamily.

YZGD from Paenibacillus thiaminolyticus is a novel bifunctional enzyme with both PLPase (pyridoxal phosphatase) and Nudix (nucleoside diphosphate x) hydrolase activities. The PLPase activity is catalysed by the HAD (haloacid dehalogenase) superfamily motif of the enzyme, and the Nudix hydrolase activity is catalysed by the conserved Nudix signature sequence within a separate portion of the enzyme, as confirmed by site-directed mutagenesis. YZGD's phosphatase activity is very specific, with pyridoxal phosphate being the only natural substrate, while YZGD's Nudix activity is just the opposite, with YZGD being the most versatile Nudix hydrolase characterized to date. YZGD's Nudix substrates include the CDP-alcohols (CDP-ethanol, CDP-choline and CDP-glycerol), the ADP-coenzymes (NADH, NAD and FAD), ADP-sugars, TDP-glucose and, to a lesser extent, UDP- and GDP-sugars. Regardless of the Nudix substrate, one of the products is always a nucleoside monophosphate, suggesting a role in nucleotide salvage. Both the PLPase and Nudix hydrolase activities require a bivalent metal cation, but while PLPase activity is supported by Co2+, Mg2+, Zn2+ and Mn2+, the Nudix hydrolase activity is Mn2+-specific. YZGD's phosphatase activity is optimal at an acidic pH (pH 5), while YZGD's Nudix activities are optimal at an alkaline pH (pH 8.5). YZGD is the first enzyme reported to be a member of both the HAD and Nudix hydrolase superfamilies, the first PLPase to be recognized as a member of the HAD superfamily and the first Nudix hydrolase capable of hydrolysing ADP-x, CDP-x and TDP-x substrates with comparable substrate specificity.

Reactions of site-differentiated [Fe4S4]2+, 1+ clusters with sulfonium cations: reactivity analogues of biotin synthase and other members of the S-adenosylmethionine enzyme family.

The first examples of reduced 3:1 site-differentiated Fe(4)S(4) clusters have been synthesized as [Fe(4)S(4)(LS(3))(SR')](3-) (R=Et, Ph) by chemical reduction of previously reported [Fe(4)S(4)(LS(3))(SR')](2-) clusters, and isolated as NBu(4)(+) salts. The reduced clusters were characterized by electrochemistry and EPR, 1H NMR, and Mössbauer spectroscopies. The reaction of oxidized clusters with the sulfonium ions [PhMeSCH(2)R](+) (R=COPh, p-C(6)H(4)CN) in acetonitrile results in electrophilic attack on coordinated thiolate and production of PhSMe and R'SCH(2)R when the reaction occurs at the unique cluster site. The reactions of reduced clusters with these substrates were examined in relation to the reductive cleavage of the cofactor S-adenosylmethionine, the first step in the catalytic cycle of biotin synthase. Product analysis indicated a approximately 4:1 ratio of reductive cleavage to electrophilic attack. The cleavage products are PhSMe, R'SCH(2)R, and RCH(3) for both clusters, and also PhMeS=CHR and RCH(2)CH(2)R from secondary reactions when the sulfonium cation is [PhMeSCH(2)COPh](+) and [PhMeSCH(2)-p-C(6)H(4)CN](+), respectively. Reaction schemes for reductive cleavage based on product distributions are presented. These results parallel those previously reported for homoleptic [Fe(4)S(4)(SR')(4)](2-,3-) clusters and demonstrate that site-differentiated clusters sustain a high percentage of reductive cleavage, a necessary result in the context of biotin synthase activity preceding an investigation of the mode of binding of sulfonium substrates and inhibitors at the unique iron site. [LS(3)=1,3,5-tris[(4,6-dimethyl-3-mercaptophenyl)thio]-2,4,6-tris(p-tolylthio)benzene(3-)].

The first complete identification of a diastereomeric catalyst-substrate (alkoxide) species in an enantioselective ketone hydrogenation. Mechanistic investigations.

The enantioselective hydrogenations of the dialkyl 3,3-dimethyloxaloacetate ketone substrates (2, 3, and 4; alkyl = Me, (i)Pr, and (t)Bu, respectively) were catalyzed by [Ru((R)-BINAP)(H)(MeCN)(n)(sol)(3-n)](BF(4)) (1, n = 0-3, sol = THF or MeOH, (R)-BINAP = (R)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) in up to 82% ee (R). Reaction of the active catalyst 1 with 1 equiv of substrate (2, 3, or 4) in THF or MeOH solution formed the diastereomeric catalyst-alkoxide complexes [Ru((R)-BINAP)(MeCN)(OCH(CO(2)R)-(C(CH(3))(2)CO(2)R))](BF(4)) (5/6 R = Me, 8/9 R = (i)Pr, and 10 R = (t)Bu, respectively) via hydride addition to the ketone carbonyl carbon and ruthenium addition to oxygen. The absolute configurations at the alkoxide groups ((R)- for the major diastereomers 5, 8, and 10) were determined via cleavage of the ruthenium-alkoxide bond with 1 equiv of HBF(4).OEt(2). The solution structures of the major diastereomer catalyst-alkoxide complexes (5, 8, and 10) were unambiguously determined by variable-temperature NMR spectroscopy. The major diastereomers (5, 8, and 10) had the same absolute configuration as the major product enantiomers from the catalytic hydrogenation of 2, 3, and 4 with 1 as catalyst. The ratio of major to minor alkoxide diastereomers was similar to the ee of the catalytic hydrogenation. The catalyst-alkoxide complexes are formed at temperatures as low as -30 degrees C with no other precursors or intermediates observed by NMR showing that ketone-hydride insertion is likely not the turnover limiting step of the catalytic hydrogenation. Results from the stoichiometric hydrogenolysis of 5/6, 8/9, or 10 indicate that their formation is rapid and only partially reversible prior to the irreversible hydrogenolysis of the ruthenium-oxygen bond. The stereoselectivities of the formation and hydrogenolysis of 5/6, 8/9, and 10 sum up to equal the stereoselectivities of the respective catalytic hydrogenations of 2, 3, and 4. The rates of the hydrogenolysis were consistent with these diastereomers being true catalytic intermediates.