RESUMO
The [3 + 2] or [4 + 2] annulation of α,ß-unsaturated aldimines with alkenes via ß'- or γ-allylic C(sp3)-H activation is, in principle, an atom-efficient route for the synthesis of five- or six-membered-ring cycloalkylamines, which are important structural motifs in numerous natural products, bioactive molecules, and pharmaceuticals. However, such a transformation has remained undeveloped to date probably due to the lack of suitable catalysts. We report herein for the first time the regio- and diastereoselective [3 + 2] and [4 + 2] annulations of α,ß-unsaturated imines with alkenes via allylic C(sp3)-H activation by half-sandwich rare-earth catalysts having different metal ion sizes. The reaction of α-methyl-substituted α,ß-unsaturated aldimines with alkenes by a C5Me4SiMe3-ligated scandium catalyst took place in a trans-diastereoselective [3 + 2] annulation fashion via C(sp3)-H activation at the α-methyl group (ß'-position), exclusively affording alkylidene-functionalized cyclopentylamines with excellent trans-diastereoselectivity. In contrast, the reaction of ß-methyl-substituted α,ß-unsaturated aldimines with alkenes by a C5Me5-ligated cerium catalyst proceeded in a cis-diastereoselective [4 + 2] annulation fashion via γ-allylic C(sp3)-H activation, selectively yielding multisubstituted 2-cyclohexenylamines with excellent cis-diastereoselectivity. The mechanistic details of these transformations have been elucidated by deuterium-labeling experiments, kinetic isotope effect studies, and the isolation and transformations of key reaction intermediates. This work offers an efficient and selective protocol for the synthesis of a new family of cycloalkylamine derivatives, featuring 100% atom efficiency, high regio- and diastereoselectivity, broad substrate scope, and an unprecedented reaction mechanism.
RESUMO
INTRODUCTION: Post-thrombectomy intraparenchymal hyperdensity (PTIH) in patients with acute ischemic stroke is a common CT sign, making it difficult for physicians to distinguish intracerebral hemorrhage in the early post-thrombectomy period. The aim of this study was to develop an effective model to differentiate intracerebral hemorrhage from contrast extravasation in patients with PTIH. METHODS: We retrospectively collected information on patients who underwent endovascular thrombectomy at two stroke centers between August 2017 and January 2023. A total of 222 patients were included in the study, including 118 patients in the development cohort, 52 patients in the internal validation cohort, and 52 patients in the external validation cohort. The nomogram was constructed using R software based on independent predictors derived from the multivariate logistic regression analysis, including clinical factors and CT texture features extracted from hyperdense areas on CT images. The performance and accuracy of the derived nomogram were assessed by the area under the receiver operating characteristic curve (AUC-ROC) and calibration curves. Additionally, decision curve analysis was conducted to appraise the clinical utility of the nomogram. RESULTS: Our nomogram was derived from two clinical factors (ASPECT score and onset to reperfusion time) and two CT texture features (variance and uniformity), with AUC-ROC of 0.943, 0.930, and 0.937 in the development, internal validation, and external validation cohorts, respectively. Furthermore, the calibration plot exhibited a strong agreement between the predicted outcome and the actual outcome. In addition, the decision curve analysis revealed the clinical utility of the nomogram in accurately predicting hemorrhage in patients with PTIH. CONCLUSION: The developed nomogram, based on clinical factors and CT texture features, proves to be effective in distinguishing intracerebral hemorrhage from contrast extravasation in patients with PTIH.
Assuntos
Hemorragia Cerebral , Extravasamento de Materiais Terapêuticos e Diagnósticos , AVC Isquêmico , Nomogramas , Valor Preditivo dos Testes , Trombectomia , Humanos , Masculino , Feminino , Estudos Retrospectivos , Idoso , Trombectomia/efeitos adversos , Hemorragia Cerebral/diagnóstico por imagem , Hemorragia Cerebral/etiologia , AVC Isquêmico/diagnóstico por imagem , AVC Isquêmico/terapia , AVC Isquêmico/etiologia , Pessoa de Meia-Idade , Extravasamento de Materiais Terapêuticos e Diagnósticos/diagnóstico por imagem , Extravasamento de Materiais Terapêuticos e Diagnósticos/etiologia , Diagnóstico Diferencial , Reprodutibilidade dos Testes , Meios de Contraste , Resultado do Tratamento , Técnicas de Apoio para a Decisão , Idoso de 80 Anos ou mais , Fatores de Risco , Tomografia Computadorizada por Raios XRESUMO
INTRODUCTION: Currently, futile reperfusion (FR) is becoming a major challenge in the endovascular treatment of patients with acute ischemic stroke (AIS). The relationship between serum uric acid (SUA) and FR has not been investigated. This study aims to determine the relationship between SUA and FR using propensity score matching (PSM) analysis. METHODS: A total of 441 patients with AIS undergoing mechanical thrombectomy (MT) between August 2017 and January 2023 were included and divided into two groups based on the median SUA (297.4 µmol/L). Two groups were balanced using PSM analysis at a 1:1 ratio. The standardized mean difference (SMD) were used to assess the efficacy of the matching. Finally, 158 patients with low SUA (≤ 297.4 µmol/L) were matched with 158 patients with high SUA (>297.4 µmol/L). Predictors of FR were analyzed by multivariate logistic regression analysis in the PSM cohort. RESULTS: After PSM, patients with low SUA (≤ 297.4 µmol/L) had a significant higher incidence of FR (72.8 %, 115/158) than patients with high SUA (>297.4 µmol/L) (48.1 %, 76/158) (P<0.001). Multivariate logistic regression analysis in the PSM cohort showed that low SUA (≤ 297.4 µmol/L) was an independent risk factor for the efficacy of reperfusion (OR: 6.403, 95 % CI: 3.123-13.129, P<0.001), suggesting that patients with SUA ≤ 297.4 µmol/L have a 6.403 times higher risk of FR than patients with SUA>297.4 µmol/L. CONCLUSION: The results of this study suggest that low SUA (≤ 297.4 µmol/L) at admission increases the risk of FR in AIS patients undergoing MT by PSM analysis.
Assuntos
AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Ácido Úrico , AVC Isquêmico/diagnóstico , AVC Isquêmico/terapia , AVC Isquêmico/complicações , Pontuação de Propensão , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/terapia , Trombectomia/efeitos adversosRESUMO
Hyperuricemia (HUA) is strongly associated with the increasing prevalence of obesity, but the underlying mechanism remains elusive. Dysfunction of brown adipose tissue (BAT) could lead to obesity. However, studies on the role of HUA on BAT are lacking. Our retrospective clinical analysis showed that serum uric acid (UA) is significantly associated with BAT in humans. To investigate the role of UA in regulating BAT function, we used UA to treat primary brown adipocytes (BACs) in vitro and established HUA mice. In vitro results showed that HUA suppressed thermogenic gene expression and oxygen consumption rate. Accordingly, HUA mice exhibited lower energy expenditure and body temperature, with larger lipid droplets and lower thermogenic gene expression. These results demonstrate that HUA inhibits BAT thermogenic capacity in vitro and in vivo. To further elucidate the mechanism of UA on adipocytes, mRNA-sequencing analysis was performed and screened for "AMP-activated protein kinase (AMPK) signaling pathway" and "mitochondrial biogenesis." Further tests in vivo and in vitro showed that the phosphorylation of AMPK was suppressed by HUA. Activation of AMPK alleviated the inhibition of AMPK phosphorylation by HUA and increased mitochondrial biogenesis, subsequently restoring the impaired BAT thermogenic capacity in vitro and vivo. Thus, we confirmed that HUA suppresses mitochondrial biogenesis by regulating AMPK, thereby inhibiting BAT thermogenic capacity. Taken together, our study identifies UA as a novel regulator of BAT thermogenic capacity, providing a new strategy to combat obesity.NEW & NOTEWORTHY To investigate the effect and mechanism of UA on BAT thermogenic capacity, we established HUA models in vitro and in vivo, and performed RNA sequencing analysis. Our results revealed that HUA suppresses mitochondrial biogenesis by regulating AMPK, thereby inhibiting BAT thermogenic capacity. Taken together, our study identifies UA as a novel regulator of BAT thermogenic capacity, providing a new strategy to combat obesity.
Assuntos
Proteínas Quinases Ativadas por AMP , Tecido Adiposo Marrom , Humanos , Camundongos , Animais , Tecido Adiposo Marrom/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Ácido Úrico/farmacologia , Ácido Úrico/metabolismo , Estudos Retrospectivos , Adipócitos Marrons , Obesidade/metabolismo , TermogêneseRESUMO
The asymmetric hydrophosphination of cyclopropenes with phosphines is of much interest and importance, but has remained hardly explored to date probably because of the lack of suitable catalysts. We report here the diastereo- and enantioselective hydrophosphination of 3,3-disubstituted cyclopropenes with phosphines by a chiral lanthanocene catalyst bearing the C2 -symmetric 5,6-dioxy-4,7-trans-dialkyl-substituted tetrahydroindenyl ligands. This protocol offers a selective and efficient route for the synthesis of a new family of chiral phosphinocyclopropane derivatives, featuring 100 % atom efficiency, good diastereo- and enantioselectivity, broad substrate scope, and no need for a directing group.
RESUMO
The [2+2] cycloaddition of allenes with alkenes is of much interest and importance as a straightforward route for the construction of four-membered carbocycles but has remained much underexplored to date. Herein we report for the first time the intermolecular regio- and diastereoselective formal [2+2] cycloaddition of a wide range of allenes with amino-functionalized alkenes by half-sandwich rare-earth catalysts. The reaction proceeded through an allene C(sp2 )-H activation mechanism initiated by the site-selective deprotonation of the allene unit by a rare-earth metal alkyl species followed by alkene insertion into the resulting metal-allenyl bond and the subsequent intramolecular cycloaddition to an allene C=C bond. This protocol offers a unique route for the synthesis of a new family of cyclobutane and cyclobutene derivatives which were difficult to access previously.
RESUMO
The catalytic enantioselective construction of three-dimensional molecular architectures from planar aromatics such as quinolines is of great interest and importance from the viewpoint of both organic synthesis and drug discovery, but there still exist many challenges. Here, we report the scandium-catalyzed asymmetric dearomative spiro-annulation of quinolines with alkynes. This protocol offers an efficient and selective route for the synthesis of spiro-dihydroquinoline derivatives containing a quaternary carbon stereocenter with an unprotected N-H group from readily accessible quinolines and diverse alkynes, featuring high yields, high enantioselectivity, 100% atom-efficiency, and broad substrate scope. Experimental and density functional theory studies revealed that the reaction proceeded through the C-H activation of the 2-aryl substituent in a quinoline substrate by a scandium alkyl (or amido) species followed by alkyne insertion into the Sc-aryl bond and the subsequent dearomative 1,2-addition of the resulting scandium alkenyl species to the CâN unit in the quinoline moiety. This work opens a new avenue for the dearomatization of quinolines, leading to efficient and selective construction of spiro molecular architectures that were previously difficult to access by other means.
RESUMO
The study of new C-H silylation reagents and reactions remains an important topic. We reported that under Rh catalysis, silacyclobutanes (SCBs) for the first time were able to react with C(sp2)-H and C(sp3)-H bonds, however the underlying reasons for such a new reactivity were not understood. Through this combined computational and experimental study on C-H silylation with SCBs, we not only depict a reaction pathway that fully accounts for the reactivity and all the experimental findings but also streamline a more efficient catalyst that significantly improves the reaction rates and yields. Our key findings include: (1) the active catalytic species is a [Rh]-H as opposed to the previously proposed [Rh]-Cl; (2) the [Rh]-H is generated via a reductive elimination/ß-hydride (ß-H) elimination sequence, as opposed to previously proposed endocyclic ß-H elimination; (3) the regio- and enantio-determining steps are identified; (4) and of the same importance, the discretely synthesized [Rh]-H is shown to be a more efficient catalyst. This work suggests that the [Rh]-H/diphosphine system should find further applications in C-H silylations involving SCBs.
RESUMO
The preparation of chiral monohydrosilanes remains a rarely achieved goal. To this end a Rh-catalyzed desymmetrization of dihydrosilanes by way of intramolecular C(sp2 )-H functionalization under simple and mild conditions has now been developed. This method provides easy access to a broad range of chiral monohydrosilanes in good yields with excellent enantioselectivities (up to >99 % ee). The resulting monohydrosilanes constitute a good platform to access stereogenic silicon compounds, as well as useful compounds to probe silicon stereochemistry.
RESUMO
Micro-electromechanical systems comprising antiferroelectric layers can offer both actuation and transduction to integrated technologies. Micro-cantilevers based on the (Pb0.97La0.02)(Zr0.95Ti0.05)O3 (PLZT) antiferroelectric thick film are fabricated by the micro-nano manufacturing process, to utilize the effect of phase transition induced strain and sharp phase switch of antiferroelectric materials. When micro-cantilevers made of antiferroelectric thick films were driven by sweep voltages, there were two resonant peaks corresponding to the natural frequency shift from 27.8 to 27.0 kHz, before and after phase transition. This is the compensation principle for the PLZT micro-cantilever to tune the natural frequency by the amplitude modulation of driving voltage, rather than of frequency modulation. Considering the natural frequency shift about 0.8 kHz and the frequency tuning ability about 156 Hz/V before the phase transition, this can compensate the frequency shift caused by increasing temperature by tuning only the amplitude of driving voltage, when the ultrasonic micro-transducer made of antiferroelectric thick films works for such a long period. Therefore, antiferroelectric thick films with hetero-structures incorporated into PLZT micro-cantilevers not only require a lower driving voltage (no more than 40 V) than rival bulk piezoelectric ceramics, but also exhibit better performance of frequency invariability, based on the amplitude modulation.
RESUMO
Sjögren's syndrome (SjS) and systemic lupus erythematosus (SLE) are common systemic autoimmune diseases, which impact not only patient health but also their quality of life. miRNA-146a is a microRNA that participates in the pathophysiology of SjS and SLE. In this investigation, we conducted a meta-analysis to determine the relationship of miR-146a to primary SjS (PSS) and to SLE. The following databases were interrogated; Pubmed, Cochrane Central Register of Controlled Trials, WANFANG, Chinese National Knowledge Infrastructure, and WEIPU. Standard mean difference with 95% confidence intervals (CI) were used to study the relationship between miRNA-146a expression and thee diseases by random-effects model. A total of six studies, with 158 cases and 124 controls were included for the meta-analysis. The meta-analysis shows that miRNA-146a expression is associated with the risk of PSS (MD = 6.32, p = 0.005). No relationship between miR-146a expression and SLE was identified (MD = -0.86, p = 0.26). SLE subgroup analysis (peripheral blood mononuclear cells and serum) confirmed this result. The risk for PSS is related to miR-146a expression, while miRNA-146a expression is not related to SLE. As such, miRNA-146a may serve as a novel biomarker for the diagnosis of PSS, but not SLE.
Assuntos
Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/genética , MicroRNAs/metabolismo , Síndrome de Sjogren/genética , Estudos de Casos e Controles , Feminino , Marcadores Genéticos , Humanos , Leucócitos Mononucleares/metabolismo , Masculino , Polimorfismo de Nucleotídeo Único , Qualidade de Vida , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de RiscoRESUMO
We report a method to construct chiral tetraorganosilicons by tandem silacyclobutane (SCB) desymmetrization-dehydrogenative silylations. A wide array of dibenzosiloles with stereogenic quaternary silicon centers were obtained in good yields and enantioselectivities up to 93 % ee. Chiral TMS-segphos was found to be a superior ligand in terms of reactivity and enantioselectivity.
RESUMO
Silacyclobutane was discovered to be an efficient C-H bond silylation reagent. Under the catalysis of Rh(I) /TMS-segphos, silacyclobutane undergoes sequential C-Si/C-H bond activations, affording a series of π-conjugated siloles in high yields and regioselectivities. The catalytic cycle was proposed to involve a rarely documented endocyclic ß-hydride elimination of five-membered metallacycles, which after reductive elimination gave rise to a Si-Rh(I) species that is capable of C-H activation.
RESUMO
Reported herein is the rhodium-catalyzed enantioselective C-H bond silylation of the cyclopentadiene rings in Fe and Ru metallocenes. Thus, in the presence of (S)-TMS-Segphos, the reactions took place under very mild conditions to afford metallocene-fused siloles in good to excellent yields and with eeâ values of up to 97%. During this study it was observed that the steric hindrance of chiral ligands had a profound influence on the reactivity and enantioselectivity of the reaction, and might hold the key to accomplishing conventionally challenging asymmetric C-H silylations.
Assuntos
Compostos Férricos/química , Compostos Organometálicos/química , Compostos Organometálicos/síntese química , Ródio/química , Silanos/química , Catálise , Estrutura Molecular , EstereoisomerismoRESUMO
Siloles represent an important emerging class of photoluminescent materials. Reported herein is a new synthetic strategy involving a tandem cyclization/Si-C activation reaction featuring high efficiency, wide substrate scope, and practical utility. This method enabled the first synthesis of benzofuran siloles as well as rapid access to conjugated siloles. During the course of the study we also uncovered an unusual yet general Si-C(sp(2)) activation in the presence of πâ acids.
Assuntos
Carbono/química , Ródio/química , Silanos/síntese química , Silício/química , Catálise , Ciclização , Compostos Heterocíclicos/química , Teoria Quântica , Silanos/químicaRESUMO
Background: Post-thrombectomy intraparenchymal hyperdensity (PTIH) in patients with acute anterior circulation large vessel occlusion is a common CT sign associated with a higher incidence of futile reperfusion (FR). We aimed to develop a nomogram to predict FR specifically in patients with PTIH. Methods: We retrospectively collected information on patients with acute ischemic stroke who underwent endovascular thrombectomy (EVT) at two stroke centers. A total of 398 patients with PTIH were included to develop and validate the nomogram, including 214 patients in the development cohort, 92 patients in the internal validation cohort and 92 patients in the external validation cohort. The nomogram was developed according to the independent predictors obtained from multivariate logistic regression analysis, including clinical factors and CT texture features extracted from hyperdense areas on CT images within half an hour after EVT. The performance of the nomogram was evaluated with integrated discrimination improvement (IDI), category-free net reclassification improvement (NRI), the area under the receiver operating characteristic curve (AUC-ROC), calibration plots, and decision curve analyses for discrimination, calibration ability, and clinical net benefits, respectively. Results: Our nomogram was constructed based on three clinical factors (age, NIHSS score and ASPECT score) and two CT texture features (entropy and kurtosis), with AUC-ROC of 0.900, 0.897, and 0.870 in the development, internal validation, and external validation cohorts, respectively. NRI and IDI further validated the superior predictive ability of the nomogram compared to the clinical model. The calibration plot revealed good consistency between the predicted and the actual outcome. The decision curve indicated good positive net benefit and clinical validity of the nomogram. Conclusion: The nomogram enables clinicians to accurately predict FR specifically in patients with PTIH within half an hour after EVT and helps to formulate more appropriate treatment plans in the early post-EVT period.
RESUMO
INTRODUCTION: Elevated levels of serum uric acid (SUA) are strongly associated with several components of the metabolic syndrome, particularly obesity. Previous studies have reported the correlation between SUA levels, xanthine oxidoreductase (XOR) activity, and the imbalanced adipokine levels that are characteristic of obesity. In this study, we explored the effect of febuxostat on circulating adipokine profiles in patients with overweight or obesity and asymptomatic hyperuricemia. METHODS: This study was a single-center, randomized and controlled clinical trial that enrolled 130 participants with asymptomatic hyperuricemia and obesity. 117 participants were included in the final analysis, with 60 participants in the febuxostat group and 57 in the control group. We compared the circulating adipokine levels at 3 and 6 months, including high molecular weight (HMW) adiponectin, chemerin, omentin, (monocyte chemotactic protein-1) MCP-1, asprosin, fibroblast growth factor 21 (FGF21), neuregulin-4 (Nrg4), leptin, resistin, vaspin, visfatin, adipsin, and assessed the correlation between changes in adipokine levels (Δadipokines) and changes in XOR activity (ΔXOR) after febuxostat treatment. RESULTS: The results showed that an increase in HMW adiponectin and omentin levels and a decrease in chemerin and asprosin levels at 3 or 6 months compared to the control group. Additionally, a positive correlation was observed between ΔXOR activity and Δasprosin. Furthermore, after adjusting for ΔTG (triglyceride) and ΔSUA (serum uric acid) in multiple linear regression analyses, we found that ΔXOR activity was independently correlated with Δasprosin. CONCLUSION: This study may provide important evidence that febuxostat could alleviate the imbalance in circulating adipokine levels in patients with overweight or obesity and asymptomatic hyperuricemia. Furthermore, we observed a positive correlation between changes in asprosin levels and changes in XOR activity after febuxostat treatment.
RESUMO
OBJECTIVE: Futile reperfusion (FR) is becoming a major challenge in the treatment of patients with acute ischaemic stroke (AIS) undergoing endovascular thrombectomy. This study aims to determine the dose-response relationship between low-density lipoprotein cholesterol (LDL-C) levels and the risk of FR in patients with AIS undergoing endovascular thrombectomy and to investigate potential mediators. METHODS: A total of 614 patients with AIS undergoing endovascular thrombectomy were enrolled and divided into five groups according to quintiles of LDL-C levels: Q1(≤2.27â¯mmol/l), Q2 (2.27-2.5â¯mmol/l), Q3 (2.5-2.59â¯mmol/l), Q4 (2.59-2.97â¯mmol/l) and Q5 (≥2.97â¯mmol/l). Associations between LDL-C levels and the risk of FR and stroke-associated pneumonia (SAP) were estimated using multivariate logistic regression models. Restricted cubic spline curves were used to describe the dose-response relationship between LDL-C levels and the risk of FR and SAP. Mediation effect analysis was performed in R software with 100 bootstrap samples. RESULTS: After adjustment for confounders, both low and high LDL-C levels were significantly associated with a higher risk of FR compared with the reference group (Q3). We observed a U-shaped association between LDL-C levels and the risk of FR (P for nonlinear =0.012). Mediation analysis showed that the association between LDL-C levels and the risk of FR was 29.7â¯% (95â¯% CI: 2.96â¯%-75.0â¯%, P=0.02) mediated by SAP. CONCLUSIONS: We found a U-shaped association between LDL-C levels and the risk of FR that was mediated by SAP. Clinicians should note that in AIS patients undergoing endovascular thrombectomy, lower LDL-C levels are not always better.
Assuntos
LDL-Colesterol , Procedimentos Endovasculares , AVC Isquêmico , Pneumonia , Trombectomia , Humanos , Masculino , Feminino , AVC Isquêmico/cirurgia , AVC Isquêmico/sangue , AVC Isquêmico/complicações , LDL-Colesterol/sangue , Idoso , Trombectomia/métodos , Pessoa de Meia-Idade , Procedimentos Endovasculares/métodos , Pneumonia/sangue , Pneumonia/complicações , Reperfusão/métodos , Idoso de 80 Anos ou mais , Fatores de Risco , Acidente Vascular Cerebral/cirurgia , Acidente Vascular Cerebral/sangueRESUMO
BACKGROUND: Coronary artery disease (CAD) is a prevalent cardiovascular condition, and numerous studies have linked gut bacterial imbalance to CAD. However, the relationship of gut fungi, another essential component of the intestinal microbiota, with CAD remains poorly understood. METHODS: In this cross-sectional study, we analyzed fecal samples from 132 participants, split into 31 healthy controls and 101 CAD patients, further categorized into stable CAD (38), unstable angina (41), and acute myocardial infarction (22) groups. We conducted internal transcribed spacer 1 (ITS1) and 16S sequencing to examine gut fungal and bacterial communities. FINDINGS: Based on ITS1 analyses, Ascomycota and Basidiomycota were the dominant fungal phyla in all the groups. The α diversity of gut mycobiome remained unaltered among the control group and CAD subgroups; however, the structure and composition of the mycobiota differed significantly with the progression of CAD. The abundances of 15 taxa gradually changed with the occurrence and progression of the disease and were significantly correlated with major CAD risk factor indicators. The mycobiome changes were closely linked to gut microbiome dysbiosis in patients with CAD. Furthermore, disease classifiers based on gut fungi effectively identified subgroups with different degrees of CAD. Finally, the FUNGuild analysis further categorized these fungi into distinct ecological guilds. INTERPRETATION: In conclusion, the structure and composition of the gut fungal community differed from healthy controls to various subtypes of CAD, revealing key fungi taxa alterations linked to the onset and progression of CAD. Our study highlights the potential role of gut fungi in CAD and may facilitate the development of novel biomarkers and therapeutic targets for CAD. FUNDING: This work was supported by the grants from the National Natural Science Foundation of China (No. 82170302, 92168117, 82370432), National clinical key specialty construction project- Cardiovascular Surgery, the Reform and Development Program of Beijing Institute of Respiratory Medicine (No. Ggyfz202417, Ggyfz202308), the Beijing Natural Science Foundation (No. 7222068); and the Clinical Research Incubation Program of Beijing Chaoyang Hospital Affiliated to Capital Medical University (No. CYFH202209).
Assuntos
Doença da Artéria Coronariana , Microbioma Gastrointestinal , Micobioma , Humanos , Doença da Artéria Coronariana/microbiologia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Estudos Transversais , Fezes/microbiologia , Metagenômica/métodos , Fungos/genética , Fungos/classificação , Fungos/isolamento & purificação , Índice de Gravidade de Doença , Disbiose/microbiologia , Estudos de Casos e Controles , RNA Ribossômico 16S/genética , AdultoRESUMO
We report a series of new 9-oxime ether non-ketolides, including 3-hydroxyl, 3-O-acyl and 3-O-alkyl clarithromycin derivatives, and thiophene-containing ketolides 1b-1d. Unlike previously reported ketolide 1a, none of them is comparable to telithromycin. A molecular modeling study was performed to gain insight into the binding mode of alkylides 17-20 with bacterial rRNA and to rationalize the great disparity of their SAR. The 3-O-sidechains of 19 and 20 point to the so-called hydrophilic side of the macrolide ring, as seen in clarithromycin. In contrast, the 3-O-sidechains of 17 and 18 bend to the backside, the so-called hydrophobic side of the macrolide ring. The results clearly indicated the alkylides with improved antibacterial activity might possess a novel binding mode, which is different from clarithromycin and the alkylides with poor activity.