18 research outputs found
Association of Candidate Gene Polymorphisms With Chronic Kidney Disease: Results of a Case-Control Analysis in the Nefrona Cohort
Chronic kidney disease (CKD) is a major risk factor for end-stage renal disease, cardiovascular disease and premature death. Despite classical clinical risk factors for CKD and some genetic risk factors have been identified, the residual risk observed in prediction models is still high. Therefore, new risk factors need to be identified in order to better predict the risk of CKD in the population. Here, we analyzed the genetic association of 79 SNPs of proteins associated with mineral metabolism disturbances with CKD in a cohort that includes 2, 445 CKD cases and 559 controls. Genotyping was performed with matrix assisted laser desorption ionizationtime of flight mass spectrometry. We used logistic regression models considering different genetic inheritance models to assess the association of the SNPs with the prevalence of CKD, adjusting for known risk factors. Eight SNPs (rs1126616, rs35068180, rs2238135, rs1800247, rs385564, rs4236, rs2248359, and rs1564858) were associated with CKD even after adjusting by sex, age and race. A model containing five of these SNPs (rs1126616, rs35068180, rs1800247, rs4236, and rs2248359), diabetes and hypertension showed better performance than models considering only clinical risk factors, significantly increasing the area under the curve of the model without polymorphisms. Furthermore, one of the SNPs (the rs2248359) showed an interaction with hypertension, being the risk genotype affecting only hypertensive patients. We conclude that 5 SNPs related to proteins implicated in mineral metabolism disturbances (Osteopontin, osteocalcin, matrix gla protein, matrix metalloprotease 3 and 24 hydroxylase) are associated to an increased risk of suffering CKD
Association of candidate gene polymorphisms with chronic kidney disease : Results of a case-control analysis in the NEFRONA cohort
Chronic kidney disease (CKD) is a major risk factor for end-stage renal disease, cardiovascular disease and premature death. Despite classical clinical risk factors for CKD and some genetic risk factors have been identified, the residual risk observed in prediction models is still high. Therefore, new risk factors need to be identified in order to better predict the risk of CKD in the population. Here, we analyzed the genetic association of 79 SNPs of proteins associated with mineral metabolism disturbances with CKD in a cohort that includes 2,445 CKD cases and 559 controls. Genotyping was performed with matrix assisted laser desorption ionization-time of flight mass spectrometry. We used logistic regression models considering different genetic inheritance models to assess the association of the SNPs with the prevalence of CKD, adjusting for known risk factors. Eight SNPs (rs1126616, rs35068180, rs2238135, rs1800247, rs385564, rs4236, rs2248359, and rs1564858) were associated with CKD even after adjusting by sex, age and race. A model containing five of these SNPs (rs1126616, rs35068180, rs1800247, rs4236, and rs2248359), diabetes and hypertension showed better performance than models considering only clinical risk factors, significantly increasing the area under the curve of the model without polymorphisms. Furthermore, one of the SNPs (the rs2248359) showed an interaction with hypertension, being the risk genotype affecting only hypertensive patients. We conclude that 5 SNPs related to proteins implicated in mineral metabolism disturbances (Osteopontin, osteocalcin, matrix gla protein, matrix metalloprotease 3 and 24 hydroxylase) are associated to an increased risk of suffering CKD
Effect of the Phosphine Steric and Electronic Profile on the Rh-Promoted Dehydrocoupling of Phosphine-Boranes
[Image: see text] The electronic and steric effects in the stoichiometric dehydrocoupling of secondary and primary phosphine鈥揵oranes H(3)B路PR(2)H [R = 3,5-(CF(3))(2)C(6)H(3); p-(CF(3))C(6)H(4); p-(OMe)C(6)H(4); adamantyl, Ad] and H(3)B路PCyH(2) to form the metal-bound linear diboraphosphines H(3)B路PR(2)BH(2)路PR(2)H and H(3)B路PRHBH(2)路PRH(2), respectively, are reported. Reaction of [Rh(L)(畏(6)-FC(6)H(5))][BAr(F)(4)] [L = Ph(2)P(CH(2))(3)PPh(2), Ar(F) = 3,5-(CF(3))(2)C(6)H(3)] with 2 equiv of H(3)B路PR(2)H affords [Rh(L)(H)(蟽,畏-PR(2)BH(3))(畏(1)-H(3)B路PR(2)H)][BAr(F)(4)]. These complexes undergo dehydrocoupling to give the diboraphosphine complexes [Rh(L)(H)(蟽,畏(2)-PR(2)路BH(2)PR(2)路BH(3))][BAr(F)(4)]. With electron-withdrawing groups on the phosphine鈥揵orane there is the parallel formation of the products of B鈥揚 cleavage, [Rh(L)(PR(2)H)(2)][BAr(F)(4)], while with electron-donating groups no parallel product is formed. For the bulky, electron rich, H(3)B路P(Ad)(2)H no dehydrocoupling is observed, but an intermediate Rh(I) 蟽 phosphine鈥揵orane complex is formed, [Rh(L){畏(2)-H(3)B路P(Ad)(2)H}][BAr(F)(4)], that undergoes B鈥揚 bond cleavage to give [Rh(L){畏(1)-H(3)B路P(Ad)(2)H}{P(Ad)(2)H}][BAr(F)(4)]. The relative rates of dehydrocoupling of H(3)B路PR(2)H (R = aryl) show that increasingly electron-withdrawing substituents result in faster dehydrocoupling, but also suffer from the formation of the parallel product resulting from P鈥揃 bond cleavage. H(3)B路PCyH(2) undergoes a similar dehydrocoupling process, and gives a mixture of stereoisomers of the resulting metal-bound diboraphosphine that arise from activation of the prochiral P鈥揌 bonds, with one stereoisomer favored. This diastereomeric mixture may also be biased by use of a chiral phosphine ligand. The selectivity and efficiencies of resulting catalytic dehydrocoupling processes are also briefly discussed
Intermediates in the Rh-catalysed dehydrocoupling of phosphine-borane.
Active species, product distributions and a suggested catalytic cycle are reported for the dehydrocoupling of the phosphine-borane H(3)B路P(t)Bu(2)H to give HP(t)Bu(2)BH(2)P(t)Bu(2)BH(3) using the [Rh(COD)(2)][BAr(F)(4)] pre-catalyst
Intermediates in the Rh-catalysed dehydrocoupling of phosphine-borane.
Active species, product distributions and a suggested catalytic cycle are reported for the dehydrocoupling of the phosphine-borane H(3)B路P(t)Bu(2)H to give HP(t)Bu(2)BH(2)P(t)Bu(2)BH(3) using the [Rh(COD)(2)][BAr(F)(4)] pre-catalyst
Revealing the P-B coupling event in the rhodium catalysed dehydrocoupling of phosphine-boranes H3B center dot PR2H (R = Bu-t, Ph)
We demonstrate that [Rh(畏6-FC6H5)(Ph2PCH2CH2CH2PPh2 )][BArF4] is a competent catalyst for the dehydrocoupling of H3B路PR2H to give H3B路PR2BH2路PR2H (R = Ph, tBu). The isolation of intermediates (R = tBu, Ph) and kinetic/isotopic labelling experiments (for R = Ph) point to a mechanism, for R = Ph, in which the rate-limiting process for dehydrocoupling involves B-H activation, while the turnover limiting process for catalysis involves the substitution of the oligomeric product at the metal, which forms a strong chelate complex with a Rh(iii) centre, by H3B路PPh2H. When R = tBu no chelate product complex forms, and it is speculated that the dehydrocoupling process now becomes turnover limiting. These observations provide, for the first time we believe, data on the P-B bond forming events that are central to the dehydrocoupling and dehydropolymerisation of phosphine-boranes. This journal is 漏 The Royal Society of Chemistry 2013
Effect of the phosphine steric and electronic profile on the Rh-promoted dehydrocoupling of phosphine-boranes.
The electronic and steric effects in the stoichiometric dehydrocoupling of secondary and primary phosphine-boranes H3B路PR2H [R = 3,5-(CF3)2C6H3; p-(CF3)C6H4; p-(OMe)C6H4; adamantyl, Ad] and H3B路PCyH2 to form the metal-bound linear diboraphosphines H3B路PR2BH2路PR2H and H3B路PRHBH2路PRH2, respectively, are reported. Reaction of [Rh(L)(畏(6)-FC6H5)][BAr(F)4] [L = Ph2P(CH2)3PPh2, Ar(F) = 3,5-(CF3)2C6H3] with 2 equiv of H3B路PR2H affords [Rh(L)(H)(蟽,畏-PR2BH3)(畏(1)-H3B路PR2H)][BAr(F)4]. These complexes undergo dehydrocoupling to give the diboraphosphine complexes [Rh(L)(H)(蟽,畏(2)-PR2路BH2PR2路BH3)][BAr(F)4]. With electron-withdrawing groups on the phosphine-borane there is the parallel formation of the products of B-P cleavage, [Rh(L)(PR2H)2][BAr(F)4], while with electron-donating groups no parallel product is formed. For the bulky, electron rich, H3B路P(Ad)2H no dehydrocoupling is observed, but an intermediate Rh(I) 蟽 phosphine-borane complex is formed, [Rh(L){畏(2)-H3B路P(Ad)2H}][BAr(F)4], that undergoes B-P bond cleavage to give [Rh(L){畏(1)-H3B路P(Ad)2H}{P(Ad)2H}][BAr(F)4]. The relative rates of dehydrocoupling of H3B路PR2H (R = aryl) show that increasingly electron-withdrawing substituents result in faster dehydrocoupling, but also suffer from the formation of the parallel product resulting from P-B bond cleavage. H3B路PCyH2 undergoes a similar dehydrocoupling process, and gives a mixture of stereoisomers of the resulting metal-bound diboraphosphine that arise from activation of the prochiral P-H bonds, with one stereoisomer favored. This diastereomeric mixture may also be biased by use of a chiral phosphine ligand. The selectivity and efficiencies of resulting catalytic dehydrocoupling processes are also briefly discussed
Bis(phosphine)boronium salts. Synthesis, structures and coordination chemistry.
The synthesis of a range of bis(phosphine)boronium salts is reported [(R2HP)2BH2][X] (R = Ph, (t)Bu, Cy) in which the counter anion is also varied (X(-) = Br(-), [OTf](-), [BAr(F)4](-), Ar(F) = 3,5-(CF3)2C6H3). Characterization in the solid-state by X-ray diffraction suggests there are weak hydrogen bonds between the PH units of the boronium cation and the anion (X(-) = Br(-), [OTf](-)), while solution NMR spectroscopy also reveals hydrogen bonding occurs in the order [BAr(F)4](-) < [OTf](-) < Br(-). [(Ph2HP)2BH2][BAr(F)4] reacts with RhH(PPh3)3, by elimination of H2, forming [Rh(魏(1),畏-PPh2BH2路PPh2H)(PPh3)2][BAr(F)4] which shows a 尾-B-agostic interaction from the resulting base stabilised phosphino-borane ligand. Alternatively such ligands can be assembled directly on the metal centre by reaction of in situ generated {Rh(PPh3)3}(+) and Ph2HP路BH3 to afford [Rh(魏(1),畏-PPh2BH2路PPh3)(PPh3)2][BAr(F)4], which was characterised by X-ray crystallography. Addition of H3B路PPh2H to the well-defined 16-electron "T-shaped" complex [Rh(P(i)Bu3)2(PPh3)][BAr(F)4] (characterised by X-ray crystallography) formed of a mixture of base-stabilised phosphino borane ligated complexes [Rh(魏(1),畏-PR2BH2路PR3)(PR3)2][BAr(F)4] (R = (i)Bu or Ph). These last observations may lend clues to the formation of bis(phosphine)boronium salts in the catalytic dehydrocoupling reaction of phosphine boranes as mediated by Rh(I) compounds
Dehydrocoupling of dimethylamine borane catalyzed by Rh(PCy3)2H2Cl.
The Rh(III) species Rh(PCy3)2H2Cl is an effective catalyst (2 mol %, 298 K) for the dehydrogenation of H3B路NMe2H (0.072 M in 1,2-F2C6H4 solvent) to ultimately afford the dimeric aminoborane [H2BNMe2]2. Mechanistic studies on the early stages in the consumption of H3B路NMe2H, using initial rate and H/D exchange experiments, indicate possible dehydrogenation mechanisms that invoke turnover-limiting N-H activation, which either precedes or follows B-H activation, to form H2B鈺怤Me2, which then dimerizes to give [H2BNMe2]2. An additional detail is that the active catalyst Rh(PCy3)2H2Cl is in rapid equilibrium with an inactive dimeric species, [Rh(PCy3)H2Cl]2. The reaction of Rh(PCy3)2H2Cl with [Rh(PCy3)H2(H2)2][BAr(F)4] forms the halide-bridged adduct [Rh(PCy3)2H2(渭-Cl)H2(PCy3)2Rh][BAr(F)4] (Ar(F) = 3,5-(CF3)2C6H3), which has been crystallographically characterized. This dinuclear cation dissociates on addition of H3B路NMe2H to re-form Rh(PCy3)2H2Cl and generate [Rh(PCy3)2H2(畏(2)-H3B路NMe2H)][BAr(F)4]. The fate of the catalyst at low catalyst loadings (0.5 mol %) is also addressed, with the formation of an inactive borohydride species, Rh(PCy3)2H2(畏(2)-H2BH2), observed. On addition of H3B路NMe2H to Ir(PCy3)2H2Cl, the Ir congener Ir(PCy3)2H2(畏(2)-H2BH2) is formed, with concomitant generation of the salt [H2B(NMe2H)2]Cl
Intermolecular Alkyne Hydroacylation. Mechanistic Insight from the Isolation of the Vinyl Intermediate That Precedes Reductive Elimination
The isolation of the branched alkenyl intermediate that directly precedes reductive elimination of the final 伪,尾-unsaturated ketone product is reported for the hydroacylation reaction between the alkyne HC鈮Ar F (Ar F = 3,5-(CF 3) 2C 6H 3) and the 尾-S-substituted aldehyde 2-(methylthio)benzaldehyde: [Rh(fac-魏 3-DPEphos)(C(=CH 2)Ar F)(C(O)C 6H 4SMe) 2][CB 11H 12]. The structure of this intermediate shows that, in this system at least, hydride migration rather than acyl migration occurs. Kinetic studies on the subsequent reductive elimination to form the crystallographically characterized ketone-bound product [Rh(cis-魏 2-DPEphos)(畏 2:畏 2, 魏 1-H 2C=C(Ar F)C(=O)(C 6H 4SMe)][CB 11H 12] yield the following activation parameters for reductive elimination, which follows first-order kinetics (k obs = (6.14 卤 0.04) 脳 10 -5 s -1, 324 K): 螖H 搂 = 95 卤 2 kJ mol -1, 螖S 搂 = -32 卤 7 J K -1 mol -1, 螖G 搂(298 K) = 105 卤 4 kJ mol -1. Mechanistic studies, including selective deuteration experiments, show that hydride insertion is not reversible and also reveal that an interesting isomerization process is occurring between the two branched alkenyl protons that is suggested to occur via a metallocyclopropene intermediate. During catalysis, the consumption of substrates and evolution of products follow pseudo zero-order kinetics. The observation of both linear and branched products under stoichiometric and catalytic regimes, in combination with kinetic modeling, allows for an overall mechanistic scheme to be presented. Partitioning of linear and branched pathways at the hydride insertion step occurs with an approximate 2:1 selectivity, while reductive elimination of the linear product is at least 3 orders of magnitude faster than that from the branched. An explanation for the large difference in rate of reductive elimination in this system, as recently outlined by Goldman, Krogh-Jespersen, and Brookhart, is that steric crowding in branched intermediates can slow C-C reductive elimination even though such species are higher in energy than their linear analogues, if the rotation of the vinyl group to the appropriate orientation is inhibited by steric crowding in the branched isomers. 漏 2012 American Chemical Society