Rhodium and ruthenium complexes of methylene-bridged, P-stereogenic, unsymmetrical diphosphanes.

Enantiopure P-stereogenic methylphosphane-boranes (SP)-P(BH3)PhArMe (ArMe; Ar = 1-naphthyl (NpMe), and 2-biphenylyl (BiphMe)) have been used to prepare diphosphanes of the type ArPhPCH2PR2 (R = Ph, iPr or tBu; ArR). The ligands have been reacted with [Rh(COD)2]BF4 to furnish the corresponding six monochelated [Rh(COD)(ArR)]BF4 organometallic compounds (RhArR) or, depending on the reaction conditions, the bis(chelated) coordination compound [Rh(BiphiPr)2]BF4 as a mixture of cis and trans isomers. The crystal structure of cis-[Rh(BiphiPr)2]BF4 was obtained. The coordination of the BiphR with [RuCl(µ-Cl)(η6-p-cymene)2]2 under different conditions produced cationic chelated complexes of the type [RuCl(η6-p-cymene)(κ2-BiphR)]PF6 (RuBiphR) and the neutral monocoordinated complex [RuCl2(η6-p-cymene)(κ1-BiphPh)] (RuBiphPh') with the uncoordinated P-stereogenic moiety. The Rh(I) complexes were used in the catalytic hydrogenation of functionalized olefins and the Ru(II) complexes were tested in the transfer hydrogenation of acetophenone. Both precursors displayed good activities with moderate enantioselectivities.

Base-assisted synthesis of 4-pyridinate gold(I) metallaligands: a study of their use in self-assembly reactions.

The synthesis of di- and tritopic gold(i) metallaligands of the type [(Au4-py)2(µ2-diphosphane)] (diphosphane = bis(diphenylphosphanyl)isopropane or dppip (1), 1,2-bis(diphenylphosphanyl)ethane or dppe (2), 1,3-bis(diphenylphosphanyl)propane or dppp (3) and 1,4-bis(diphenylphosphanyl)butane or dppb (4)) and [(Au4-py)3(µ3-triphosphane)] (triphosphane = 1,1,1-tris(diphenylphosphanylmethyl)ethane or triphos (5) and 1,3,5-tris(diphenylphosphanyl)benzene or triphosph (6)) from [(AuCl)2(µ2-diphosphane)] or [(AuCl)3(µ3-triphosphane)] and 4-pyridylboronic acid in the presence of Cs2CO3 has been conducted. Interestingly, when [(AuCl)2(µ2-dppm)] (dppm = bis(diphenylphosphanyl)methane) was used as a starting material, the cyclic tetranuclear gold(i) compound [(Au4-py)2(CH)2{µ2-Au(PPh2)2}2] (I) was obtained instead. All the products have been characterized by IR and multinuclear NMR spectroscopy, mass spectrometry and elemental analysis and in the case of 1, 3, 5 and I by X-ray crystallography, which showed the presence of aurophilic interactions in all of them. The obtained metallaligands have been used as building blocks in self-assembly reactions with cis-blocked palladium or platinum acceptor moieties producing [2 + 2] metallamacrocycles or trigonal bipyramidal (TBP) [2 + 3] metallacages in good yields. The photophysical properties of both the metallaligands and the corresponding assemblies have been investigated.

Self-Assembled, Highly Positively Charged, Allyl-Pd Crowns: Cavity-Pocket-Driven Interactions of Fluoroanions.

A series of dodecanuclear highly positively charged homo- and heterometallamacrocycles [{Pd(η3 -2-Me-C3 H4 )}6 (4-PPh2 py)12 {M2 (tpbz)}3 ]18+ (M=Pd, Pt; tpbz=1,2,4,5-tetrakis(diphenylphosphanyl)benzene were synthesized by the quantitative self-assembly of {Pd(η3 -2-Me-C3 H4 )}+ , {M2 (tpbz)}4+ and 4-PPh2 py moieties in 2:1:4 molar ratio. The cationic assemblies were obtained as salts of different fluorinated anions with diverse sizes and electronic properties, namely BF4 - , PF6 - , SbF6 - and CF3 SO3 - . The new crown-like metallamacrocycles showed remarkable differences in their NMR spectra due to the presence of the different counteranions. On the basis of the observed variations, the metallacycles have been tested as catalytic precursors in allylic alkylation reactions. The anion-dependent activity and selectivity has been analysed and compared with that of the corresponding monometallic allylic corners [Pd(η3 -2-Me-C3 H4 )(4-PPh2 py)2 ]X (X=BF4 - , PF6 - , SbF6 - , CF3 SO3 - ). DFT calculations have been employed in order to help to the interpretation of the experimental data and to model the anion-crown interactions.

Assessing the strengths and weaknesses of the Clinical Frailty Scale through correlation with a frailty index.

BACKGROUND: Care for the elderly patient is a challenge that geriatricians now share with other medical specialties. Frailty has emerged as a key concept. Due to its simplicity and applicability, the Clinical Frailty Scale (CFS) is gaining increasing acceptance. AIM: Compare the CFS with the Frail-VIG index (IF-VIG), an index based on the accumulation of deficits and developed on the basis of comprehensive geriatric assessment. METHODS: Cross-sectional and single-center study carried out at the Acute Geriatric Unit of a University Hospital. Patients consecutively recruited on admission over a 6-month period (n = 184). The concurrent validity of the CFS was measured by assessing the concordance between the two measurement methods. The degree of association was determined by applying a linear regression model, calculating the Pearson correlation coefficient (r). RESULTS: The prevalence of frailty was 91.8%. A mean IF-VIG score of 0.41 (SD ± 0.14) was found. The two most frequently recorded CFS categories were 6 and 7. An effective correlation was established (r = 0.706, p < 0.001). In the cohort with severe dementia, the association fell (r = 0.442). In the whole population, it rose adding Charlson index score (r = 0.747). CONCLUSIONS: The strong correlation of the CFS with a frailty index supports its use. Incorporating comorbidity into the physical function domains of the CFS improved the correlation. However, the CFS was unsuitable in patients with dementia. To infer prognosis, in categories 6 and 7, the situational diagnosis should be extended with more discriminative tools.

Bond Dissociation Energies of Metallo-supramolecular Building Blocks: Insight from Fragmentation of Selectively Self-Assembled Heterometallic Metallo-supramolecular Aggregates.

A series of selectively self-assembled metallo-supramolecular square-like macrocycles with unsymmetric ditopic linkers and two different types of metal corners, i.e., {Pd(η3-2-Me-C3H4)} and {M(dppp)} with dppp = 1,3-bis(diphenylphosphino)propane and M = Pd2+ or Pt2+, have been studied in the gas phase using collision-induced dissociation. The aggregates show distinct fragmentation patterns determined by ligand length, i.e, aggregate size, and type of metal corner. Information on relative binding strength can be deduced. This is of particular interest for (methylallyl)Pd as a relatively new building block in metallo-supramolecular chemistry. The phosphane end of the unsymmetric ligand connected to (η3-2-Me-C3H4)Pd is bound significantly stronger than its pyridine end to (dppp)Pt and (dppp)Pd. These results are corroborated by DFT calculations.

Polypyridyl-functionalizated alkynyl gold(i) metallaligands supported by tri- and tetradentate phosphanes.

A series of alkynyl gold(i) tri and tetratopic metallaligands of the type [Au3(C[triple bond, length as m-dash]C-R)3(µ3-triphosphane)] (R = 2,2'-bipyridin-5-yl or C10H7N2, 2,2':6',2''-terpyridin-4-yl or C15H10N3; triphosphane = 1,1,1-tris(diphenylphosphanyl)ethane or triphos, 1,3,5-tris(diphenylphosphanyl)benzene or triphosph) and [Au4(C[triple bond, length as m-dash]C-R)4(µ4-tetraphosphane)] (R = C10H7N2, C15H10N3; tetraphosphane = tetrakis(diphenylphosphanylmethyl)methane or tetraphos, 1,2,3,5-tetrakis(diphenylphosphanyl)benzene or tpbz, tetrakis(diphenylphosphaneylmethyl)-1,2-ethylenediamine or dppeda) were obtained in moderate to good yields. All complexes could be prepared by a reaction between the alkynyl gold(i) polymeric species [Au(C[triple bond, length as m-dash]C-R)]n and the appropriate polyphosphane. An alternative strategy that required the previous synthesis of the appropriate acetylacetonate precursors [Aun(acac)n(µn-polyphosphane)] ("acac method") was assayed, nevertheless only the polyacac derivatives [Au3(acac)3(µ3-triphosphane)] (triphosphane = triphos and triphosph) and [Au4(acac)4(µ4-tetraphos)] could be isolated and characterized. All compounds were characterized by IR, multinuclear NMR spectroscopy and ESI(+) mass spectrometry. The X-ray crystal structure of complexes [Au4(C[triple bond, length as m-dash]C-C10H7N2)4(µ4-tetraphos)] and [Au4(C[triple bond, length as m-dash]C-C10H7N2)4(µ4-tpbz)] showed the involvement of all the gold atoms in close intramolecular AuAu contact as well as intermolecular π stacking interactions between the aromatic rings of the polypyridyl ligands. The photophysical properties of the synthesized compounds were carefully studied and used as a probe of their possible use as multidentate ligands for Cu(i) and Zn(ii). The UV-Vis speciation studies of the complexation reactions were conducted via metal titration and, in most cases the dangling units of the ligand were found to behave in a fairy independent manner. While in the case of Cu(i) multiple equilibria exist in solution a single complex is detected for Zn(ii) under the conditions studied.

Subacute Cutaneous Lupus Erythematosus: Clinical Characteristics, Disease Associations, Treatments, and Outcomes in a Series of 90 Patients at Mayo Clinic, 1996-2011.

OBJECTIVE: To characterize the clinical presentation, laboratory studies, disease associations, and treatments of subacute cutaneous lupus erythematosus (SCLE). PATIENTS AND METHODS: A retrospective review of 90 patients with SCLE at Mayo Clinic from January 1, 1996, through October 28, 2011, was performed. RESULTS: The mean patient age at diagnosis was 61 years; 64 patients (71%) were women, and 11 cases (12%) were drug induced (1996-2000, no drug-induced cases; 2001-2005, 2 cases; 2006-2011, 9 cases). Seventeen of 59 patients (29%) with available data were smokers at the time of diagnosis. The SCLE lesions were photodistributed in 75 patients (83%), and 52 (58%) had papulosquamous morphologic findings. Anti-Ro/SS-A positivity was present in 84 of 85 patients tested (99%), whereas 32 of the 85 patients (38%) tested positive for anti-La/SS-B. Associated autoimmune connective tissue diseases included Sjögren syndrome (n=13, 14%) and systemic lupus erythematosus (SLE) (n=8, 9%). Eighteen patients (20%) had at least 4 American College of Rheumatology criteria for SLE; 1 had lupus nephritis, and none had neurologic or notable hematologic sequelae. The most common therapy was hydroxychloroquine, with a complete response noted in 34 of 46 patients (74%) with available follow-up data. CONCLUSION: Twenty-eight percent of patients with SCLE (n=25) had an associated autoimmune connective tissue disease, although the severe sequelae of SLE, such as nephritis, were rare. The frequency of drug-induced SCLE increased during the study. Most patients responded to treatment with hydroxychloroquine.

Kinetico-mechanistic insights on the assembling dynamics of allyl-cornered metallacycles: the Pt-Npy bond is the keystone.

The square-like homo- and heterometallamacrocycles [{Pd(η(3) -2-Me-C3 H4 )(L(n) )2 }2 {M(dppp)}2 ](CF3 SO3 )6 (dppp=1,3-bis(diphenylphosphino)propane) and [{Pd(η(3) -2-Me-C3 H4 )(L(1) )2 }2 {M(PPh3 )2 }2 ](CF3 SO3 )6 [py=pyridine, M=Pd, Pt, L(n=) 4-PPh2 py (L(1) ), 4-C6 F4 PPh2 py (L(2) )] containing allyl corners were synthesised by antisymbiotic self-assembly of the different palladium and platinum metallic corners and the ambidentate N,P ligands. All the synthesised assemblies displayed a complex dynamic behaviour in solution, the rate of which is found to be dependent on the electronic and/or steric nature of the different building blocks. A kinetico-mechanistic study by NMR line shape analysis of the dynamics of some of these assemblies was undertaken in order to determine the corresponding thermal activation parameters. Both an enhanced thermodynamic stability and slower dynamics were observed for platinum-pyridine-containing species when compared with their palladium analogues. Time-dependent NMR spectroscopy in combination with ESI mass spectrometry was used to study the exchange between the assemblies and their building blocks, as well as that occurring between different metallamacrocycles. Preliminary studies were carried out on the activity of some of the metallamacrocyclic compounds as catalytic precursors in the allylic substitution reaction, and the results compared with that of the monometallic allylic corner [Pd(η(3) -2-Me-C3 H4 )(L(1) )2 ](+) .

Dinuclear pyridine-4-thiolate-bridged rhodium and iridium complexes as ditopic building blocks in molecular architecture.

A series of dinuclear pyridine-4-thiolate (4-Spy)-bridged rhodium and iridium compounds [M(µ-4-Spy)(diolef)]2 [diolef = 1,5-cyclooctadiene (cod), M = Rh (1), Ir (2); diolef = 2,5-norbornadiene (nbd), M = Rh (3)] were prepared by the reaction of Li(4-Spy) with the appropriate compound [M(µ-Cl)(diolef)]2 (M = Rh, Ir). The dinuclear compound [Rh(µ-4-Spy)(CO)(PPh3)]2 (4) was obtained by the reaction of [Rh(acac)(CO)(PPh3)] (acac = acetylacetonate) with 4-pySH. Compounds 1-4 were assessed as metalloligands in self-assembly reactions with the cis-blocked acceptors [M(cod)(NCCH3)2](BF4) [M = Rh (a), Ir (b)] and [M(H2O)2(dppp)](OTf)2 [M = Pd (c), Pt (d); dppp = 1,3-bis(diphenylphosphino)propane]. The homometallic hexanuclear metallomacrocycles [{M2(µ-4-Spy)2(cod)2}2{M(cod)}2](BF4)2 (M = Rh [(1a)2], Ir [(2b)2]) and the heterometallic hexanuclear metallomacrocycles [{Rh2(µ-4-Spy)2(cod)2}2{Ir(cod)}2](BF4)2 [(1b)2], [{Rh2(µ-4-Spy)2(cod)2}2{M'(dppp)}2](OTf)4 (M' = Pd [(1c)2], Pt [(1d)2]), and [{Ir2(µ-4-Spy)2(cod)2}2{M'(dppp)}2](OTf)4 (M' = Pd [(2c)2], Pt [(2d)2]) were obtained. NMR spectroscopy in combination with electrospray ionization mass spectrometry was used to elucidate the nature of the metalloligands and their respective supramolecular assemblies. Most of the synthesized species were found to be nonrigid in solution, and their fluxional behavior was studied by variable-temperature (1)H NMR spectroscopy. An X-ray diffraction study of the assemblies (1a)2 and (1d)2 revealed the formation of rectangular (9.6 Å × 6.6 Å) hexanuclear metallomacrocycles with alternating dinuclear (Rh2) and mononuclear (Rh or Pt) corners. The hexanuclear core is supported by four pyridine-4-thiolate linkers, which are bonded through the thiolate moieties to the dinuclear rhodium units, exhibiting a bent-anti arrangement, and through the peripheral pyridinic nitrogen atoms to the mononuclear corners.

Calcinosis cutis in autoimmune connective tissue diseases.

Calcinosis cutis is a chronic condition involving insoluble calcified deposits of the skin and subcutaneous tissue. It is commonly associated with autoimmune connective tissue diseases and can be a source of pain and functional disability. The likelihood of developing calcinosis varies among the autoimmune connective tissue diseases, with systemic sclerosis and dermatomyositis being the most commonly associated. Identification of therapy for this challenging disorder has been hampered by a paucity of large controlled trials. Although there is no uniformly effective treatment for calcinosis cutis, several surgical and medical therapies have demonstrated varying degrees of benefit in the treatment of calcinosis, including surgical excision, laser therapy, extracorporeal shock wave lithotripsy, diltiazem, minocycline, colchicine, and topical sodium thiosulfate, along with others. Recommendations for the diagnosis and therapy of calcinosis cutis in patients with autoimmune connective tissue diseases are discussed.

Differentiation of chronic lymphocytic leukemia B cells into immunoglobulin secreting cells decreases LEF-1 expression.

Lymphocyte enhancer binding factor 1 (LEF-1) plays a crucial role in B lineage development and is only expressed in B cell precursors as B cell differentiation into mature B and plasma cells silences its expression. Chronic lymphocytic leukemia (CLL) cells aberrantly express LEF-1 and its expression is required for cellular survival. We hypothesized that modification of the differentiation status of CLL cells would result in loss of LEF-1 expression and eliminate the survival advantage provided by its aberrant expression. In this study, we first established a methodology that induces CLL cells to differentiate into immunoglobulin (Ig) secreting cells (ISC) using the TLR9 agonist, CpG, together with cytokines (CpG/c). CpG/c stimulation resulted in dramatic CLL cell phenotypic and morphologic changes, expression of cytoplasmic Ig, and secretion of light chain restricted Ig. CpG/c stimulation also resulted in decreased CLL cell LEF-1 expression and increased Blimp-1 expression, which is crucial for plasma cell differentiation. Further, Wnt pathway activation and cellular survival were impaired in differentiated CLL cells compared to undifferentiated CLL cells. These data support the notion that CLL can differentiate into ISC and that this triggers decreased leukemic cell survival secondary to the down regulation of LEF-1 and decreased Wnt pathway activation.

Selective induction of DNA repair pathways in human B cells activated by CD4+ T cells.

Greater than 75% of all hematologic malignancies derive from germinal center (GC) or post-GC B cells, suggesting that the GC reaction predisposes B cells to tumorigenesis. Because GC B cells acquire expression of the highly mutagenic enzyme activation-induced cytidine deaminase (AID), GC B cells may require additional DNA repair capacity. The goal of this study was to investigate whether normal human B cells acquire enhanced expression of DNA repair factors upon AID induction. We first demonstrated that several DNA mismatch repair, homologous recombination, base excision repair, and ATR signaling genes were overexpressed in GC B cells relative to naïve and memory B cells, reflecting activation of a process we have termed somatic hyperrepair (SHR). Using an in vitro system, we next characterized activation signals required to induce AID expression and SHR. Although AID expression was induced by a variety of polyclonal activators, SHR induction strictly required signals provided by contact with activated CD4+ T cells, and B cells activated in this manner displayed reduced levels of DNA damage-induced apoptosis. We further show the induction of SHR is independent of AID expression, as GC B cells from AID-/-mice retained heightened expression of SHR proteins. In consideration of the critical role that CD4+ T cells play in inducing the SHR process, our data suggest a novel role for CD4+ T cells in the tumor suppression of GC/post-GC B cells.

LEF-1 is a prosurvival factor in chronic lymphocytic leukemia and is expressed in the preleukemic state of monoclonal B-cell lymphocytosis.

The canonical Wnt signaling pathway is pathogenic in a variety of cancers. We previously identified aberrant expression of the Wnt pathway transcription factor and target gene lymphoid enhancer binding factor-1 (LEF1) in chronic lymphocytic leukemia (CLL). This suggested that the Wnt signaling pathway has a role in the biology of CLL. In this study, we performed a Wnt pathway analysis using gene expression profiling and identified aberrant regulation of Wnt pathway target genes, ligands, and signaling members in CLL cells. Furthermore, we identified aberrant protein expression of LEF-1 specifically in CLL but not in normal mature B-cell subsets or after B-cell activation. Using the T cell-specific transcription factor/LEF (TCF/LEF) dual luciferase reporter assay, we demonstrated constitutive Wnt pathway activation in CLL, although the pathway was inactive in normal peripheral B cells. Importantly, LEF-1 knockdown decreased CLL B-cell survival. We also identified LEF-1 expression in CD19(+)/CD5(+) cells obtained from patients with monoclonal B-cell lymphocytosis, suggesting a role for LEF-1 early in CLL leukemogenesis. This study has identified the constitutive activation and prosurvival function of LEF-1 and the Wnt pathway in CLL and uncovered a possible role for these factors in the preleukemic state of monoclonal B-cell lymphocytosis.

Expanding the cavity size: preparation of 2:1 inclusion complexes based on dinuclear square metallocycles.

The self-assembly of two new ligands based on the trans-1,2-bis(4-pyridyl)ethylene motif with palladium or platinum complexes led to quadrangular metallocycles. 1,1'-Methylenebis(4-((E)-2-(pyridin-4-yl)vinyl)pyridinium gave the square metallocycles, while the second ligand, which is less symmetrical, gave a mixture of the regioisomeric metallocyles. The metallocycles display the ideal disposition of the pi-acceptor units to maximize the pi-stacking interactions with aromatic guests. Thus, molecular recognition of pi-donor aromatic guests by square metallocycles produced the corresponding 2:1 inclusion complexes. On the other hand, starting from the mixture of regioisomers, the incorrect regioisomer rearranged to the correct metallocycle upon the addition of aromatic guests. On the basis of this behavior, a [3]catenane was obtained regioselectively from the mixture of the regioisomeric metallocycles and the appropriate cyclophane. The formation of this catenane was confirmed by NMR and X-ray crystallographic studies.

Self-assembly reactions between the cis-protected metal corners (N-N)MII (N-N = ethylenediamine, 4,4'-substituted 2,2'-bipyridine; M = Pd, Pt) and the fluorinated edge 1,4-bis(4-pyridyl)tetrafluorobenzene.

The self-assembly reactions between the fluorinated ditopic ligand 1,4-bis(4-pyridyl)tetrafluorobenzene (A) and different nitrogen-protected palladium(II) and platinum(II) complexes have been investigated. While dynamic equilibria between molecular triangles and squares were observed when the diimine compounds 4,4'-R2bipy (bipy = 2,2'-bipyridine; R = H, Me, t-Bu) were employed as ancillary ligands, only square species were obtained from ethylenediamine (en) derivatives. Characterization of the obtained metallomacrocycles was accomplished by 1H and 19F NMR spectroscopy in combination with electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry (ESI-FT-ICR). Molecular dynamics simulations (UFF) have been performed to interpret the influence of the fluorinated ring on the square/triangle relative stability. Density functional calculations using the GIAO method have been employed for the interpretation of the chemical shift assignments. The study of the ability of these compounds to act as hosts of electron-rich aromatic guests has shown that the palladium ethylenediamine square is capable of establishing this type of intermolecular interaction exclusively in aqueous media. The host-guest stoichiometry and association constants have been determinated by 1H NMR spectroscopy.

Tyrosines in the MUC1 cytoplasmic tail modulate transcription via the extracellular signal-regulated kinase 1/2 and nuclear factor-kappaB pathways.

Much of the ability of the MUC1 oncoprotein to foster tumorigenesis and tumor progression likely originates from the interaction of its cytoplasmic tail with proteins involved in oncogenic signaling. Many of these interactions are regulated by phosphorylation, as the cytoplasmic tail contains seven highly conserved tyrosines and several serine/threonine phosphorylation sites. We have developed a cell line-based model system to study the effects of tyrosine phosphorylation on MUC1 signaling, with particular emphasis on its effects on gene transcription. COS-7 cells, which lack endogenous MUC1, were stably infected with wild-type MUC1 or a MUC1 construct lacking all seven tyrosines (MUC1 Y0) and analyzed for effects on transcription mediated by the extracellular signal-regulated kinase 1/2 (ERK1/2) and nuclear factor-kappaB (NF-kappaB) pathways. COS.MUC1 Y0 cells showed heightened active ERK1/2 with increased activator protein-1 (AP-1) and signal transducer and activator of transcription 3 (STAT3) transcriptional activity; there was also a simultaneous decrease in NF-kappaB transcriptional activity and nuclear localization. These changes altered the phenotype of COS.MUC1 Y0 cells, as this line displayed increased invasion and enhanced [(3)H]thymidine incorporation. Analysis of the three lines also showed significant differences in their cell cycle profile and bromodeoxyuridine incorporation when the cells were serum starved. These data support the growing evidence that MUC1 is involved in transcriptional regulation and link MUC1 for the first time to the NF-kappaB pathway.