Síntesis y reactividad de complejos binucleares insaturados de Molibdeno con ligandos carbino

La química de los complejos carbino es un área de gran interés dentro de la química organometálica. La reactividad de estos sistemas se puede ver incrementada con la presencia de enlaces múltiples metal-metal como los que presentan los complejos [Mo2Cp2(m-CPh)(m-PCy2)(m-CO)] (I) [Mo2Cp2(m-CPh)(m-PCy2)(CO)2] (II) y [Mo2Cp2(m-CPh)(m-PCy2)(m-CO)]BF4 (4). Este último posee además un electrón desapareado que lo convierte en un sustrato interesante por la combinación de los tres factores comentados. La reacción de alquilación del complejo I resulta un método eficaz de síntesis de nuevos complejos insaturados con ligandos alcoxicarbino. La adición de dos ligandos dadores provoca una reacción de acoplamiento C-C entre ligandos carbino en el complejo [Mo2Cp2(m-COMe)(m-CPh)(m-PCy2)]BF4, para generar los compuestos [Mo2Cp2{m-eta2:eta2-C(OMe)CPh}(m-PCy2)L2]+ (L = CO, CNtBu, CNXyl), los cuales poseen en su estructura un nuevo ligando fenilmetoxiacetileno coordinado a ambos centros metálicos. La generación del radical 4 abre la posibilidad de sintetizar nuevas especies insaturadas que no pudieron ser obtenidas a partir del complejo precursor I. Este estudio confirma la elevada reactividad de la especie paramagnética con tres posiciones distintas para unión con el reactivo entrante: el centro metálico, el átomo de oxígeno del ligando carbonilo y el átomo de carbono del ligando carbino. Así, reacciona con ligandos E-H de cierta actividad química provocando diferentes tipos de acoplamientos, tales como el acoplamiento O-H en el caso del complejo hidroxicarbino [Mo2Cp2(m-COH)(m-CPh)(m-PCy2)]BF4, o el inusual acoplamiento C-P que conduce al complejo fosfinocarbeno [Mo2Cp2(m-eta1:k1,eta1-CPhPEt2)(m-PEt2)(CO)(PHEt2)]BF4. Además, reacciona con atrapadores radicalarios como NO ó Ph2S2 para generar los complejos nitrosilo y tiolato [Mo2Cp2(m-X)(m-CPh)(m-PCy2)]BF4 (X = NO, SPh), con los ligandos entrantes en disposición puente. En la reacción con Ph2S2 se forma en primer lugar el complejo carbonílico [Mo2Cp2(m-CPh)(m-PCy2)(m-SPh)(CO)]BF4, cuya gran insaturación le permite captar con rapidez una molécula de H2O para dar [Mo2Cp2(m-CPh)(m-SPh)(m-PCy2)(CO)(OH2)]BF4 o reaccionar con CO, generando entonces el complejo [Mo2Cp2(m-SPh)(m-eta1:k1,eta1-CPhPCy2)(CO)3]BF4, el cual presenta un inusual acoplamiento entre los ligandos carbino y fosfuro de la molécula. La Tesis finaliza con el estudio de la reactividad del complejo dicarbonilo II. La reacción de protonación conduce a la mezcla de dos isómeros, el complejo [Mo2Cp2(m-CPh)(m-k1:eta2-PHCy2)(CO)2]BF4 con una interacción M-H-P de tipo agóstico y el complejo carbeno [Mo2Cp2(m-eta1:eta1-CHPh)(m-PCy2)(CO)]BF4. La reacción del compuesto II con fragmentos [Au(PR3)]+, genera un único tipo de productos trans-[Mo2Cp2{m-CPhAu(PR3)}(m-PCy2)(CO)2]PF6 (R = p-Tol, Me, iPr) que evolucionan con el tiempo a los correspondientes isómeros cis. Esta diferencia con respecto a las protonaciones se puede explicar debido a impedimentos estéricos propios del reactivo utilizado. Por otro lado, el complejo II es capaz de adicionar fácilmente una molécula de alquino o un único átomo de calcógeno al enlace M-C para dar, con altos rendimientos, los correspondientes complejos [Mo2Cp2{m-eta2:eta3-C(R)C(R)CPh)}(m-PCy2)(CO)2] y [Mo2Cp2{m-eta1,k1:eta1,k1-C(Ph)E}(m-PCy2)(CO)2] (E = S, Se) respectivamente. En cambio, la adición de ligandos dadores al enlace M-M puede inducir un acoplamiento carbino-carbonilo, como se observa en la reacción con N2CPh2 para dar el cetenilo [Mo2Cp2{m-eta1:eta2-C(Ph)CO}(k1-N2CPh2)(m-PCy2)(CO)]. Los resultados presentados en esta Memoria son muy variados y novedosos, lo que se ve reflejado en el importante número de productos obtenidos, que pertenecen a más de treinta tipos estructurales diferentes. Esto demuestra la gran versatilidad sintética que ofrece la combinación en la misma molécula de dos funcionalidades de alta reactividad como son los enlaces múltiples intermetálicos y los enlaces múltiples M-C

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Optimization of adsorptive removal of α-toluic acid by CaO2 nanoparticles using response surface methodology

The present work addresses the optimization of process parameters for adsorptive removal of α-toluic acid by calcium peroxide (CaO2) nanoparticles using response surface methodology (RSM). CaO2 nanoparticles were synthesized by chemical precipitation method and confirmed by Transmission electron microscopy (TEM) and high-resolution TEM (HRTEM) analysis which shows the CaO2 nanoparticles size range of 5–15 nm. A series of batch adsorption experiments were performed using CaO2 nanoparticles to remove α-toluic acid from the aqueous solution. Further, an experimental based central composite design (CCD) was developed to study the interactive effect of CaO2 adsorbent dosage, initial concentration of α-toluic acid, and contact time on α-toluic acid removal efficiency (response) and optimization of the process. Analysis of variance (ANOVA) was performed to determine the significance of the individual and the interactive effects of variables on the response. The model predicted response showed a good agreement with the experimental response, and the coefficient of determination, (R2) was 0.92. Among the variables, the interactive effect of adsorbent dosage and the initial α-toluic acid concentration was found to have more influence on the response than the contact time. Numerical optimization of process by RSM showed the optimal adsorbent dosage, initial concentration of α-toluic acid, and contact time as 0.03 g, 7.06 g/L, and 34 min respectively. The predicted removal efficiency was 99.50%. The experiments performed under these conditions showed α-toluic acid removal efficiency up to 98.05%, which confirmed the adequacy of the model prediction

Clinical and genetic characteristics of late-onset Huntington's disease

Background: The frequency of late-onset Huntington's disease (>59 years) is assumed to be low and the clinical course milder. However, previous literature on late-onset disease is scarce and inconclusive. Objective: Our aim is to study clinical characteristics of late-onset compared to common-onset HD patients in a large cohort of HD patients from the Registry database. Methods: Participants with late- and common-onset (30–50 years)were compared for first clinical symptoms, disease progression, CAG repeat size and family history. Participants with a missing CAG repeat size, a repeat size of ≤35 or a UHDRS motor score of ≤5 were excluded. Results: Of 6007 eligible participants, 687 had late-onset (11.4%) and 3216 (53.5%) common-onset HD. Late-onset (n = 577) had significantly more gait and balance problems as first symptom compared to common-onset (n = 2408) (P <.001). Overall motor and cognitive performance (P <.001) were worse, however only disease motor progression was slower (coefficient, −0.58; SE 0.16; P <.001) compared to the common-onset group. Repeat size was significantly lower in the late-onset (n = 40.8; SD 1.6) compared to common-onset (n = 44.4; SD 2.8) (P <.001). Fewer late-onset patients (n = 451) had a positive family history compared to common-onset (n = 2940) (P <.001). Conclusions: Late-onset patients present more frequently with gait and balance problems as first symptom, and disease progression is not milder compared to common-onset HD patients apart from motor progression. The family history is likely to be negative, which might make diagnosing HD more difficult in this population. However, the balance and gait problems might be helpful in diagnosing HD in elderly patients