Synthesis of 1-indanones through the intramolecular Friedel-Crafts acylation reaction using NbCl5 as Lewis acid

The intramolecular Friedel-Crafts acylation reaction of 3-arylpropanoic acids to give 1-indanones can be effected in good yields under mild conditions (room temperature) by using niobium pentachloride. Our results indicate that NbCl5 acts both as reagent (to transform carboxylic acids into acyl chlorides) and as catalyst in the Friedel-Crafts cyclization.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenadoria de Aperfeiçoamento de Pessoal do Nível Superior (CAPES

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

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

Total synthesis of the proposed structure of nhatrangin A and analogs

Orientador: Luiz Carlos DiasTese (doutorado) - Universidade Estadual de Campinas, Instituto de QuímicaResumo: A nhatrangina A foi isolada em 2010, por Orjala e colaboradores, a partir de uma coleção vietnamita da cianobactéria marinha Lyngbya majuscula. Este policetídeo apresenta seis centros estereogênicos e sua determinação estrutural foi realizada através da análise conjunta dos espectros de RMN 1D e 2D. O objetivo principal deste trabalho foi investigar uma rota sintética convergente e flexível para a obtenção deste produto natural e checar o assinalamento estrutural proposto pelos autores do isolamento. A estrutura proposta para a nhatrangina A foi sintetizada em 19 etapas, considerando a rota linear mais longa, e rendimento global de 6,7%. As etapas chave envolveram reação aldólica, reação de Corey-Fuchs, acoplamento entre alcino e amida de Weinreb mediado por lítio, redução estereosseltiva de Noyori e reação de esterificação de Yamaguchi. Além disso, sintetizamos seis diastereoisômeros da estrutura proposta para o produto natural, utilizando a mesma estratégia sintética empregada na síntese da estrutura proposta para a nhatrangina A, no entanto nenhum destes isômeros corresponderam ao produto naturalAbstract: The nhatrangin A was isolated in 2010 by Orjala and co-workers, from a Vietnamese collection of marine cyanobacterium Lyngbya majuscula. This polyketide containing six stereogenic centers and its structure was assigned based on spectrometric and spectroscopic methods including 1D and 2D NMR experiments. The aim of this work was to investigate the convergent and flexible synthetic route for obtaining this natural product and check the structural assignment proposed by the authors of isolation. The proposed structure of nhatrangin A was synthesized in 19 steps, considering the longest linear route, and overall yield of 6.7%. The key steps involved aldol reaction, Corey-Fuchs reaction, lithium-mediated coupling between alkyne and Weinreb amide, Noyori stereoselective reduction and Yamaguchi esterification. In addition, we synthesized six diastereoisomers of the proposed structure for the natural product, using the same synthetic strategy employed in the synthesis of the proposed structure of nhatrangin A, however none of these isomers correspond to the natural productDoutoradoQuimica OrganicaDoutora em Químic

Control of 1,5 remote stereochemistry in additions of boron enolates of methylketones to aldehydes

Orientador: Luiz Carlos DiasDissertação (mestrado) - Universidade Estadual de Campinas, Instituto de QuímicaResumo: As reações aldólicas com o enolato de boro da metilcetona 44, com protetor cíclico de acetonídeo e relação trans entre os centros quirais, levaram à obtenção de adutos de aldol com níveis de seletividade variando de moderados a bons, em favor do isômero 1,5-anti. Reações aldólicas envolvendo enolatos de boro da metilcetona 45, com protetor cíclico de acetonídeo e relação cis entre os centros quirais, levaram à formação de adutos de aldol com excelentes níveis de seletividade em favor do isômero 1,5-anti. As reações aldólicas entre o enolato de boro da metilcetona 46, com protetor cíclico de silício e relação trans entre os centros quirais, levaram a obtenção de adutos de aldol com níveis de seletividade variando de moderados a bons em favor do isômero 1,5-anti. A reação aldólica entre o enolato de boro da metilcetona 47, com protetor cíclico de silício e relação cis entre os centros quirais, e pivalaldeído levou à formação do aduto de aldol em bom nível de seletividade em favor do isômero 1,5-antiAbstract: The aldol reactions of the boron enolate generated from methylketone 44 (containing a trans-acetonide), led to aldol adducts with moderate to good levels of diastereoselectivity, favoring the 1,5-anti adduct. The aldol reactions involving the boron enolate of methylketone 45 (containing a cis-acetonide) gave the corresponding aldol adducts with excellent levels of diastereoselectivity, favoring the 1,5-anti adduct. The aldol reactions of the boron enolate generated from methylketone 46 (containing a cyclic silicon protecting group and trans relationship between the chiral centers), led to the formation of aldol adducts with moderate to good levels of diastereoselectivity favoring the 1,5-anti isomer. The aldol reaction between the boron enolate prepared from methylketone 47 (containing a cyclic silicon protecting group and cis relationship between the chiral centers), led to the formation of aldol adduct with good level of diastereoselectivity favoring the 1,5-anti isomerMestradoQuimica OrganicaMestre em Químic

Enantioselective heck arylation of acyclic alkenol aryl ethers: synthetic applications and DFT investigation of the stereoselectivity

Herein we report the enantioselective Heck-Matsuda arylation of acyclic E and Z-alkenyl aryl ethers. The reactions were carried out under mild conditions affording the enantioenriched benzyl ethers in a regioselective manner, moderate to good yields (up to 73%), and in good to excellent enantiomeric ratios (up to 97:3). The enantioselective Heck-Matsuda arylation has shown a broad scope (25 examples), and some key Heck-Matsuda adducts were further converted into more complex and valuable scaffolds including their synthetic application in the synthesis of (R)-Fluoxetine, (R)-Atomoxetine, and in the synthesis of an enantioenriched benzo[c]chromene. Finally, in silico mechanistic investigations into the reaction's enantioselectivity were performed using density functional theory3624884892CNPQ - Conselho Nacional de Desenvolvimento Científico e TecnológicoFAPESP – Fundação de Amparo à Pesquisa Do Estado De São Paulo2017/21494-2; 2019/02052-4; 2015/01491-3; 2014/25770-6; 2013/07600-3; 2014/25770-6406643/2018-0; 306773/2018-

Regioselective and Stereoselective Heck–Matsuda Arylations of Trisubstituted Allylic Alkenols and Their Silyl and Methyl Ether Derivatives To Access Two Contiguous Stereogenic Centers: Expanding the Redox-Relay Process and Application in the Total Synthesis of <i>meso</i>-Hexestrol

Novel palladium-catalyzed redox-relay Heck arylation reactions of trisubstituted allylic alkenols were developed employing silyl and methyl ethers. The reactions proceeded under mild conditions in moderate to high yields in an excellent <i>anti</i> diastereoselectivity to form α,β-disubstituted methyl ketones containing two contiguous stereocenters. The new redox-relay arylations using silyl and methyl ethers of the starting alkenols demonstrate that the presence of a free hydroxyl group is not a sine qua non condition for an effective redox-relay process as previously thought. Deuterium-labeled alkenols <b>2-</b><i><b>d</b></i><b>-10a</b>, <b>2-</b><i><b>d</b></i><b>-10b</b>, and <b>2-</b><i><b>d</b></i><b>-10c</b> permitted tracking the palladium-hydride reinsertion steps in the conversion of the starting free alcohols, silyl, and methyl ethers into the corresponding methyl ketone <b>3-</b><i><b>d</b></i><b>-11a</b>, with >98% deuterium retention. Moreover, the synthetic potential of the method was demonstrated with a straightforward synthesis of the <i>meso</i>-hexestrol in 4 steps, in 41% overall yield from alkenol <b>10a</b>

Association of p16 expression with prognosis varies across ovarian carcinoma histotypes: an Ovarian Tumor Tissue Analysis consortium study.

We aimed to validate the prognostic association of p16 expression in ovarian high-grade serous carcinomas (HGSC) and to explore it in other ovarian carcinoma histotypes. p16 protein expression was assessed by clinical-grade immunohistochemistry in 6525 ovarian carcinomas including 4334 HGSC using tissue microarrays from 24 studies participating in the Ovarian Tumor Tissue Analysis consortium. p16 expression patterns were interpreted as abnormal (either overexpression referred to as block expression or absence) or normal (heterogeneous). CDKN2A (which encodes p16) mRNA expression was also analyzed in a subset (n = 2280) mostly representing HGSC (n = 2010). Association of p16 expression with overall survival (OS) was determined within histotypes as was CDKN2A expression for HGSC only. p16 block expression was most frequent in HGSC (56%) but neither protein nor mRNA expression was associated with OS. However, relative to heterogeneous expression, block expression was associated with shorter OS in endometriosis-associated carcinomas, clear cell [hazard ratio (HR): 2.02, 95% confidence (CI) 1.47-2.77, p &lt; 0.001] and endometrioid (HR: 1.88, 95% CI 1.30-2.75, p = 0.004), while absence was associated with shorter OS in low-grade serous carcinomas (HR: 2.95, 95% CI 1.61-5.38, p = 0.001). Absence was most frequent in mucinous carcinoma (50%), and was not associated with OS in this histotype. The prognostic value of p16 expression is histotype-specific and pattern dependent. We provide definitive evidence against an association of p16 expression with survival in ovarian HGSC as previously suggested. Block expression of p16 in clear cell and endometrioid carcinoma should be further validated as a prognostic marker, and absence in low-grade serous carcinoma justifies CDK4 inhibition