RESUMO
Bimolecular nucleophilic substitution (SN2) mechanisms occupy a central place in the historical development and teaching of the field of organic chemistry1. Despite the importance of SN2 pathways in synthesis, catalytic control of ionic SN2 pathways is rare and notably uncommon even in biocatalysis2,3, reflecting the fact that any electrostatic interaction between a catalyst and the reacting ion pair necessarily stabilizes its charge and, by extension, reduces polar reactivity. Nucleophilic halogenase enzymes navigate this tradeoff by desolvating and positioning the halide nucleophile precisely on the SN2 trajectory, using geometric preorganization to compensate for the attenuation of nucleophilicity4. Here we show that a small-molecule (646 Da) hydrogen-bond-donor catalyst accelerates the SN2 step of an enantioselective Michaelis-Arbuzov reaction by recapitulating the geometric preorganization principle used by enzymes. Mechanistic and computational investigations show that the hydrogen-bond donor diminishes the reactivity of the chloride nucleophile yet accelerates the rate-determining dealkylation step by reorganizing both the phosphonium cation and the chloride anion into a geometry that is primed to enter the SN2 transition state. This new enantioselective Arbuzov reaction affords highly enantioselective access to an array of H-phosphinates, which are in turn versatile P-stereogenic building blocks amenable to myriad derivatizations. This work constitutes, to our knowledge, the first demonstration of catalytic enantiocontrol of the phosphonium dealkylation step, establishing a new platform for the synthesis of P-stereogenic compounds.
RESUMO
Asymmetric transition-metal catalysis represents a powerful strategy for accessing enantiomerically enriched molecules1-3. The classical strategy for inducing enantioselectivity with transition-metal catalysts relies on direct complexation of chiral ligands to produce a sterically constrained reactive metal site that allows formation of the major product enantiomer while effectively inhibiting the pathway to the minor enantiomer through steric repulsion4. The chiral-ligand strategy has proven applicable to a wide variety of highly enantioselective transition-metal-catalysed reactions, but important scenarios exist that impose limits to its successful adaptation. Here, we report a new approach for inducing enantioselectivity in transition-metal-catalysed reactions that relies on neutral hydrogen-bond donors (HBDs)5,6 that bind anions of cationic transition-metal complexes to achieve enantiocontrol and rate enhancement through ion pairing together with other non-covalent interactions7-9. A cooperative anion-binding effect of a chiral bis-thiourea HBD is demonstrated to lead to high enantioselectivity (up to 99% enantiomeric excess) in intramolecular ruthenium-catalysed propargylic substitution reactions10. Experimental and computational mechanistic studies show the attractive interactions between electron-deficient arene components of the HBD and the metal complex that underlie enantioinduction and the acceleration effect.
RESUMO
Research in the field of asymmetric catalysis over the past half century has resulted in landmark advances, enabling the efficient synthesis of chiral building blocks, pharmaceuticals and natural products1-3. A small number of asymmetric catalytic reactions have been identified that display high selectivity across a broad scope of substrates; not coincidentally, these are the reactions that have the greatest impact on how enantioenriched compounds are synthesized4-8. We postulate that substrate generality in asymmetric catalysis is rare not simply because it is intrinsically difficult to achieve, but also because of the way chiral catalysts are identified and optimized9. Typical discovery campaigns rely on a single model substrate, and thus select for high performance in a narrow region of chemical space. Here we put forth a practical approach for using multiple model substrates to select simultaneously for both enantioselectivity and generality in asymmetric catalytic reactions from the outset10,11. Multisubstrate screening is achieved by conducting high-throughput chiral analyses by supercritical fluid chromatography-mass spectrometry with pooled samples. When applied to Pictet-Spengler reactions, the multisubstrate screening approach revealed a promising and unexpected lead for the general enantioselective catalysis of this important transformation, which even displayed high enantioselectivity for substrate combinations outside of the screening set.
Assuntos
Produtos Biológicos , Técnicas de Química Sintética , Preparações Farmacêuticas , Produtos Biológicos/síntese química , Produtos Biológicos/química , Catálise , Preparações Farmacêuticas/síntese química , Preparações Farmacêuticas/química , Estereoisomerismo , Especificidade por Substrato , Cromatografia com Fluido Supercrítico , Espectrometria de Massas , Técnicas de Química Sintética/métodosRESUMO
The identification of general and efficient methods for the construction of oligosaccharides stands as one of the great challenges for the field of synthetic chemistry1,2. Selective glycosylation of unprotected sugars and other polyhydroxylated nucleophiles is a particularly significant goal, requiring not only control over the stereochemistry of the forming bond but also differentiation between similarly reactive nucleophilic sites in stereochemically complex contexts3,4. Chemists have generally relied on multi-step protecting-group strategies to achieve site control in glycosylations, but practical inefficiencies arise directly from the application of such approaches5-7. Here we describe a strategy for small-molecule-catalyst-controlled, highly stereo- and site-selective glycosylations of unprotected or minimally protected mono- and disaccharides using precisely designed bis-thiourea small-molecule catalysts. Stereo- and site-selective galactosylations and mannosylations of a wide assortment of polyfunctional nucleophiles is thereby achieved. Kinetic and computational studies provide evidence that site-selectivity arises from stabilizing C-H/π interactions between the catalyst and the nucleophile, analogous to those documented in sugar-binding proteins. This work demonstrates that highly selective glycosylation reactions can be achieved through control of stabilizing non-covalent interactions, a potentially general strategy for selective functionalization of carbohydrates.
Assuntos
Técnicas de Química Sintética , Glicosilação , Açúcares , Catálise , Dissacarídeos/síntese química , Dissacarídeos/química , Cinética , Monossacarídeos/síntese química , Monossacarídeos/química , Estereoisomerismo , Açúcares/síntese química , Açúcares/químicaRESUMO
Autologous stem cell transplantation (ASCT) is often used as consolidation for several subtypes of peripheral T-cell lymphoma (PTCL) in first remission. However, many patients relapse after ASCT and have a very poor prognosis. There are no approved treatment options for posttransplantation maintenance or consolidation in PTCL. PD-1 blockade has demonstrated some efficacy for patients with PTCL. We, therefore, conducted a phase 2 multicenter study of the anti-PD-1 monoclonal antibody pembrolizumab after ASCT in patients with PTCL in first remission. Pembrolizumab was administered at 200 mg IV every 3 weeks for up to 8 cycles within 21 days from post-ASCT discharge (and within 60 days of stem cell infusion). The primary end point was progression-free survival (PFS) at 18 months after ASCT. Twenty-one patients were treated in this study and 67% (n = 14) completed 8 cycles of treatment. Among all patients who were evaluable, 13 of 21 were alive and achieved PFS at 18 months after ASCT, meeting the study's primary end point. The estimated 18-month PFS was 83.6% (95% confidence interval [CI], 68-100), and overall survival 94.4% (95% CI, 84-100). The toxicity profile was consistent with the known toxicity profile of pembrolizumab, with no grade 5 toxicities. In conclusion, PD-1 blockade after ASCT with pembrolizumab is feasible with a favorable safety profile and promising activity, supporting further confirmatory studies. This trial was registered at www.clinicaltrials.gov as #NCT02362997.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Linfoma de Células T Periférico , Humanos , Intervalo Livre de Doença , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Recidiva Local de Neoplasia/etiologia , Transplante Autólogo , Linfoma de Células T Periférico/tratamento farmacológico , Linfócitos T/patologia , Transplante de Células-TroncoRESUMO
We report asymmetric potassium-isothiourea-boronate-catalyzed Wittig olefinations of 4-substituted cyclohexanones with non-stabilized phosphorus ylides to afford highly enantioenriched axially chiral alkenes. The optimal catalyst features an unusual macrocyclic amide-potassium-boronate chelate. Kinetic and spectroscopic analyses are consistent with a Lewis acid mechanism for the catalytic olefination that results in the formation of the oxaphosphetane adduct under cryogenic conditions. Thermal fragmentation of the oxaphosphetane to the alkene product occurs after the reaction is complete. Computational studies indicate that cycloaddition proceeds via a stepwise mechanism involving enantiodetermining polar 1,2-addition to afford an intermediate potassium betaine complex.
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Antibodies targeting PD-1 or 4-1BB achieve objective responses in follicular lymphoma (FL), but only in a minority of patients. We hypothesized that targeting multiple immune receptors could overcome immune resistance and increase response rates in patients with relapsed/refractory FL. We therefore conducted a phase 1b trial testing time-limited therapy with different immunotherapy doublets targeting 4-1BB (utomilumab), OX-40 (ivuxolimab), and PD-L1 (avelumab) in combination with rituximab among patients with relapsed/refractory grade 1-3A FL. Patients were enrolled onto 2 of 3 planned cohorts (cohort 1 - rituximab/utomilumab/avelumab; cohort 2 - rituximab/ivuxolimab/utomilumab). 3+3 dose escalation was followed by dose expansion at the recommended phase 2 dose (RP2D). Twenty-four patients were enrolled (16 in cohort 1 and 9 in cohort 2, with one treated in both cohorts). No patients discontinued treatment due to adverse events and the RP2D was the highest dose level tested in both cohorts. In cohort 1, the objective and complete response rates were 44% and 19%, respectively (50% and 30%, respectively, at RP2D). In cohort 2, no responses were observed. The median progression-free survivals in cohorts 1 and 2 were 6.9 and 3.2 months, respectively. In cohort 1, higher density of PD-1+ tumor-infiltrating T-cells on baseline biopsies and lower density of 4-1BB+ and TIGIT+ T-cells in on-treatment biopsies were associated with response. Abundance of Akkermansia in stool samples was also associated with response. Our results support a possible role for 4-1BB agonist therapy in FL and suggest that features of the tumor microenvironment and stool microbiome may be associated with clinical outcomes (NCT03636503).
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Antineoplásicos , Linfoma Folicular , Humanos , Rituximab , Linfoma Folicular/tratamento farmacológico , Receptor de Morte Celular Programada 1 , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Antineoplásicos/uso terapêutico , Anticorpos Monoclonais/efeitos adversos , Imunoterapia , Microambiente TumoralRESUMO
The unimolecular nucleophilic substitution (SN1) mechanism features prominently in every introductory organic chemistry course. In principle, stepwise displacement of a leaving group by a nucleophile via a carbocationic intermediate enables the construction of highly congested carbon centres. However, the intrinsic instability and high reactivity of the carbocationic intermediates make it very difficult to control product distributions and stereoselectivity in reactions that proceed via SN1 pathways. Here we report asymmetric catalysis of an SN1-type reaction mechanism that results in the enantioselective construction of quaternary stereocentres from racemic precursors. The transformation relies on the synergistic action of a chiral hydrogen-bond-donor catalyst with a strong Lewis-acid promoter to mediate the formation of tertiary carbocationic intermediates at low temperature and to achieve high levels of control over reaction enantioselectivity and product distribution. This work provides a foundation for the enantioconvergent synthesis of other fully substituted carbon stereocentres.
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Química Orgânica/métodos , Carbono/química , Catálise , Ligação de Hidrogênio , Cinética , Ácidos de Lewis/química , Estereoisomerismo , TemperaturaRESUMO
A catalytic protio-semipinacol ring-expansion reaction has been developed for the highly enantioselective conversion of tertiary vinylic cyclopropyl alcohols into cyclobutanone products bearing α-quaternary stereogenic centers. The method relies on the cocatalytic effect of a chiral dual-hydrogen-bond donor (HBD) with hydrogen chloride. Experimental evidence is provided for a stepwise mechanism where protonation of the alkene generates a short-lived, high-energy carbocation, which is followed by C-C bond migration to deliver the enantioenriched product. This research applies strong acid/chiral HBD cocatalysis to weakly basic olefinic substrates and lays the foundation for further investigations of enantioselective reactions involving high-energy cationic intermediates.
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Signaling through JAK1 and/or JAK2 is common among tumor and nontumor cells within peripheral T-cell lymphoma (PTCL). No oral therapies are approved for PTCL, and better treatments for relapsed/refractory disease are urgently needed. We conducted a phase 2 study of the JAK1/2 inhibitor ruxolitinib for patients with relapsed/refractory PTCL (n = 45) or mycosis fungoides (MF) (n = 7). Patients enrolled onto 1 of 3 biomarker-defined cohorts: (1) activating JAK and/or STAT mutations, (2) ≥30% pSTAT3 expression among tumor cells by immunohistochemistry, or (3) neither or insufficient tissue to assess. Patients received ruxolitinib 20 mg PO twice daily until progression and were assessed for response after cycles 2 and 5 and every 3 cycles thereafter. The primary endpoint was clinical benefit rate (CBR), defined as the combination of complete response, partial response (PR), and stable disease lasting at least 6 months. Only 1 of 7 patients with MF had CBR (ongoing PR > 18 months). CBR among the PTCL cases (n = 45) in cohorts 1, 2, and 3 were 53%, 45%, and 13% (cohorts 1 & 2 vs 3, P = .02), respectively. Eight patients had CBR > 12 months (5 ongoing), including 4 of 5 patients with T-cell large granular lymphocytic leukemia. In an exploratory analysis using multiplex immunofluorescence, expression of phosphorylated S6, a marker of PI3 kinase or mitogen-activated protein kinase activation, in <25% of tumor cells was associated with response to ruxolitinib (P = .05). Our findings indicate that ruxolitinib is active across various PTCL subtypes and support a precision therapy approach to JAK/STAT inhibition in patients with PTCL. This trial was registered at www.clincialtrials.gov as #NCT02974647.
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Janus Quinases/metabolismo , Linfoma de Células T Periférico/tratamento farmacológico , Nitrilas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Fatores de Transcrição STAT/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Janus Quinases/antagonistas & inibidores , Linfoma de Células T Periférico/metabolismo , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/metabolismo , Resultado do Tratamento , Adulto JovemRESUMO
T-cell/histiocyte-rich large B-cell lymphoma (TCRLBCL) is an aggressive variant of diffuse large B-cell lymphoma (DLBCL) characterized by rare malignant B cells within a robust but ineffective immune cell infiltrate. The mechanistic basis of immune escape in TCRLBCL is poorly defined and not targeted therapeutically. We performed a genetic and quantitative spatial analysis of the PD-1/PD-L1 pathway in a multi-institutional cohort of TCRLBCLs and found that malignant B cells harbored PD-L1/PD-L2 copy gain or amplification in 64% of cases, which was associated with increased PD-L1 expression (P = .0111). By directed and unsupervised spatial analyses of multiparametric cell phenotypic data within the tumor microenvironment, we found that TCRLBCL is characterized by tumor-immune "neighborhoods" in which malignant B cells are surrounded by exceptionally high numbers of PD-L1-expressing TAMs and PD-1+ T cells. Furthermore, unbiased clustering of spatially resolved immune signatures distinguished TCRLBCL from related subtypes of B-cell lymphoma, including classic Hodgkin lymphoma (cHL) and DLBCL-NOS. Finally, we observed clinical responses to PD-1 blockade in 3 of 5 patients with relapsed/refractory TCRLBCL who were enrolled in clinical trials for refractory hematologic malignancies (NCT03316573; NCT01953692), including 2 complete responses and 1 partial response. Taken together, these data implicate PD-1 signaling as an immune escape pathway in TCRLBCL and also support the potential utility of spatially resolved immune signatures to aid the diagnostic classification and immunotherapeutic prioritization of diverse tumor types.
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Histiócitos/imunologia , Linfoma Difuso de Grandes Células B/imunologia , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T/imunologia , Evasão Tumoral , Antígeno B7-H1/análise , Antígeno B7-H1/imunologia , Histiócitos/patologia , Humanos , Linfoma Difuso de Grandes Células B/patologia , Receptor de Morte Celular Programada 1/análise , Linfócitos T/patologiaRESUMO
Importance: Anthracyclines treat a broad range of cancers. Basic and retrospective clinical data have suggested that use of atorvastatin may be associated with a reduction in cardiac dysfunction due to anthracycline use. Objective: To test whether atorvastatin is associated with a reduction in the proportion of patients with lymphoma receiving anthracyclines who develop cardiac dysfunction. Design, Setting, and Participants: Double-blind randomized clinical trial conducted at 9 academic medical centers in the US and Canada among 300 patients with lymphoma who were scheduled to receive anthracycline-based chemotherapy. Enrollment occurred between January 25, 2017, and September 10, 2021, with final follow-up on October 10, 2022. Interventions: Participants were randomized to receive atorvastatin, 40 mg/d (n = 150), or placebo (n = 150) for 12 months. Main Outcomes and Measures: The primary outcome was the proportion of participants with an absolute decline in left ventricular ejection fraction (LVEF) of ≥10% from prior to chemotherapy to a final value of <55% over 12 months. A secondary outcome was the proportion of participants with an absolute decline in LVEF of ≥5% from prior to chemotherapy to a final value of <55% over 12 months. Results: Of the 300 participants randomized (mean age, 50 [SD, 17] years; 142 women [47%]), 286 (95%) completed the trial. Among the entire cohort, the baseline mean LVEF was 63% (SD, 4.6%) and the follow-up LVEF was 58% (SD, 5.7%). Study drug adherence was noted in 91% of participants. At 12-month follow-up, 46 (15%) had a decline in LVEF of 10% or greater from prior to chemotherapy to a final value of less than 55%. The incidence of the primary end point was 9% (13/150) in the atorvastatin group and 22% (33/150) in the placebo group (P = .002). The odds of a 10% or greater decline in LVEF to a final value of less than 55% after anthracycline treatment was almost 3 times greater for participants randomized to placebo compared with those randomized to atorvastatin (odds ratio, 2.9; 95% CI, 1.4-6.4). Compared with placebo, atorvastatin also reduced the incidence of the secondary end point (13% vs 29%; P = .001). There were 13 adjudicated heart failure events (4%) over 24 months of follow-up. There was no difference in the rates of incident heart failure between study groups (3% with atorvastatin, 6% with placebo; P = .26). The number of serious related adverse events was low and similar between groups. Conclusions and Relevance: Among patients with lymphoma treated with anthracycline-based chemotherapy, atorvastatin reduced the incidence of cardiac dysfunction. This finding may support the use of atorvastatin in patients with lymphoma at high risk of cardiac dysfunction due to anthracycline use. Trial Registration: ClinicalTrials.gov Identifier: NCT02943590.
Assuntos
Antraciclinas , Antibióticos Antineoplásicos , Atorvastatina , Fármacos Cardiovasculares , Cardiopatias , Linfoma , Feminino , Humanos , Pessoa de Meia-Idade , Antraciclinas/efeitos adversos , Antraciclinas/uso terapêutico , Antibióticos Antineoplásicos/efeitos adversos , Antibióticos Antineoplásicos/uso terapêutico , Atorvastatina/uso terapêutico , Método Duplo-Cego , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/prevenção & controle , Estudos Retrospectivos , Volume Sistólico , Função Ventricular Esquerda , Fármacos Cardiovasculares/uso terapêutico , Linfoma/tratamento farmacológico , Cardiopatias/induzido quimicamente , Cardiopatias/fisiopatologia , Cardiopatias/prevenção & controle , Seguimentos , Masculino , Adulto , IdosoRESUMO
The mechanism of chiral hydrogen-bond donor (HBD) and hydrogen chloride (HCl) co-catalyzed Prins cyclizations was analyzed through a combination of experimental and computational methods and revealed to involve an unexpected and previously unrecognized mode of alkene activation. Kinetic and spectroscopic studies support the participation of a catalytically active HCl·HBD complex that displays reduced Brønsted acidity relative to HCl alone. Nevertheless, rate acceleration relative to the HCl-catalyzed background reaction as well as high levels of enantioselectivity are achieved. This inverse Brønsted correlation is ascribed to chloride-mediated substrate activation in the rate-limiting and enantiodetermining cyclization transition state. Density functional theory (DFT) calculations, distortion-interaction analysis, and quasiclassical dynamics simulations support a stepwise mechanism in which rate acceleration and enantioselectivity are achieved through the precise positioning of the chloride anion within the active site of the chiral thiourea to enhance the nucleophilicity of the alkene and provide transition-state stabilization through local electric field effects. This mode of selective catalysis through anion positioning likely has general implications for the design of enantioselective Brønsted acid-catalyzed reactions involving π-nucleophiles.
Assuntos
Alcenos , Tioureia , Alcenos/química , Ânions , Catálise , Cloretos , Ciclização , Halogênios , Ácido Clorídrico , Estereoisomerismo , Tioureia/químicaRESUMO
BACKGROUND: The safety and efficacy of brentuximab vedotin (BV), an antibody-drug conjugate directed to the CD30 antigen, has been assessed in several trials in patients with peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), or B-cell non-Hodgkin lymphoma (NHL). The objective of this research was to examine the relationship between CD30 expression level and clinical response to BV. PATIENTS AND METHODS: We analyzed response in patients treated with BV monotherapy in 5 prospective clinical studies in relapsed or refractory PTCL, CTCL, or B-cell NHL. CD30 expression was assessed by immunohistochemistry (IHC) using the Ber H2 antibody for 275 patients. RESULTS: Across all 5 studies, 140 (50.9%) patients had tumors with CD30 expression <10%, including 60 (21.8%) with undetectable CD30 by IHC. No significant differences were observed for any study in overall response rates between patients with CD30 expression ≥10% or <10%. Median duration of response was also similar in the CD30 ≥10% and <10% groups for all studies. CONCLUSIONS: In this analysis of studies across a range of CD30-expressing lymphomas, CD30 expression alone, as measured by standard IHC, does not predict clinical benefit from BV, making the determination of a threshold level of expression uncertain.
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Imunoconjugados , Linfoma de Células T Periférico , Brentuximab Vedotin , Humanos , Imunoconjugados/efeitos adversos , Antígeno Ki-1/metabolismo , Linfoma de Células T Periférico/tratamento farmacológico , Estudos ProspectivosRESUMO
Erdheim-Chester disease (ECD) is a rare histiocytosis that was recently recognized as a neoplastic disorder owing to the discovery of recurrent activating MAPK (RAS-RAF-MEK-ERK) pathway mutations. Typical findings of ECD include central diabetes insipidus, restrictive pericarditis, perinephric fibrosis, and sclerotic bone lesions. The histopathologic diagnosis of ECD is often challenging due to nonspecific inflammatory and fibrotic findings on histopathologic review of tissue specimens. Additionally, the association of ECD with unusual tissue tropism and an insidious onset often results in diagnostic errors and delays. Most patients with ECD require treatment, except for a minority of patients with minimally symptomatic single-organ disease. The first ECD consensus guidelines were published in 2014 on behalf of the physicians and researchers within the Erdheim-Chester Disease Global Alliance. With the recent molecular discoveries and the approval of the first targeted therapy (vemurafenib) for BRAF-V600-mutant ECD, there is a need for updated clinical practice guidelines to optimize the diagnosis and treatment of this disease. This document presents consensus recommendations that resulted from the International Medical Symposia on ECD in 2017 and 2019. Herein, we include the guidelines for the clinical, laboratory, histologic, and radiographic evaluation of ECD patients along with treatment recommendations based on our clinical experience and review of literature in the molecular era.
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Doença de Erdheim-Chester/diagnóstico , Doença de Erdheim-Chester/terapia , Ensaios Clínicos como Assunto , Doença de Erdheim-Chester/genética , Feminino , Histiocitose de Células de Langerhans/diagnóstico , Histiocitose de Células de Langerhans/genética , Histiocitose de Células de Langerhans/terapia , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Masculino , Terapia de Alvo Molecular , Mutação , Prognóstico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genéticaRESUMO
Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of lymphoproliferative disorders arising from mature T cells, accounting for about 10% of non-Hodgkin lymphomas. PTCL-not otherwise specified is the most common subtype, followed by angioimmunoblastic T-cell lymphoma, anaplastic large cell lymphoma, anaplastic lymphoma kinase-positive, anaplastic large cell lymphoma, anaplastic lymphoma kinase-negative, and enteropathy-associated T-cell lymphoma. This discussion section focuses on the diagnosis and treatment of PTCLs as outlined in the NCCN Guidelines for T-Cell Lymphomas.
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Linfadenopatia Imunoblástica , Linfoma de Células T Periférico , Linfoma de Células T , Humanos , Linfadenopatia Imunoblástica/diagnóstico , Linfadenopatia Imunoblástica/patologia , Linfadenopatia Imunoblástica/terapia , Linfoma de Células T/diagnóstico , Linfoma de Células T/terapia , Linfoma de Células T Periférico/diagnóstico , Linfoma de Células T Periférico/terapiaRESUMO
DISEASE OVERVIEW: Follicular lymphoma (FL) is generally an indolent B cell lymphoproliferative disorder of transformed follicular center B cells. FL is characterized by diffuse lymphadenopathy, bone marrow involvement, and splenomegaly. Extranodal involvement is less common. Cytopenias are relatively common but constitutional symptoms of fever, night sweats, and weight loss are uncommon in the absence of transformation to diffuse large B cell lymphoma. DIAGNOSIS: The diagnosis is based on histology from a biopsy of a lymph node or other affected tissue. Incisional biopsy is preferred over needle biopsies in order to give adequate tissue to assign grade and assess for transformation. Immunohistochemical staining is positive in virtually all cases for cell surface CD19, CD20, CD10, and monoclonal immunoglobulin, as well as cytoplasmic expression of bcl-2 protein. The overwhelming majority of cases have the characteristic t(14;18) translocation involving the IgH/bcl-2 genes. RISK STRATIFICATION: The Follicular Lymphoma International Prognostic Index (FLIPI) uses five independent predictors of inferior survival: age >60 years, hemoglobin <12 g/dL, serum LDH > normal, Ann Arbor stage III/IV, number of involved nodal areas >4. The presence of 0-1, 2, and ≥3 adverse factors defines low, intermediate, and high-risk disease. There are other clinical prognostic models but the FLIPI remains the most common. Other factors such as time to relapse of less than 2 years from chemoimmunotherapy and specific gene mutations may also be useful for prognosis. Regardless of the prognostic model used, modern therapies have demonstrably improved prognosis. RISK-ADAPTED THERAPY: Observation continues to be appropriate for asymptomatic patients with low bulk disease and no cytopenias. There is no overall survival (OS) advantage for early treatment with either chemotherapy or single-agent rituximab. For patients needing therapy, most patients are treated with chemoimmunotherapy, which has improved overall response rates (ORR), DOR, and OS. Randomized studies have shown additional benefits for maintenance of rituximab. Lenalidomide was non-inferior to chemoimmunotherapy in a randomized front-line study and, when combined with rituximab, was superior to rituximab alone in relapsed FL. Kinase inhibitors, stem cell transplantation (SCT), and chimeric antigen receptor T cells (CAR-T) are also considered for recurrent disease.
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Linfoma Folicular , Humanos , Pessoa de Meia-Idade , Linfoma Folicular/terapia , Linfoma Folicular/tratamento farmacológico , Rituximab/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , PrognósticoRESUMO
Glycosyl phosphates are shown to be activated to stereospecific nucleophilic substitution reactions by precisely tailored bis-thiourea catalysts. Enhanced reactivity and scope is observed with phosphate relative to chloride leaving groups. Stronger binding (Km) to the H-bond donor and enhanced reactivity of the complex (kcat) enables efficient catalysis with broad functional group compatibility under mild, neutral conditions.
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Catálise , Glicosilação , Fosfatos/metabolismo , Glicosilação/efeitos dos fármacos , Ligação de Hidrogênio , Ácidos de Lewis/metabolismo , Estereoisomerismo , Tioureia/metabolismoRESUMO
Cooperative asymmetric catalysis with hydrogen chloride (HCl) and chiral dual-hydrogen-bond donors (HBDs) is applied successfully to highly enantioselective Prins cyclization reactions of a wide variety of simple alkenyl aldehydes. The optimal chiral catalysts were designed to withstand the strongly acidic reaction conditions and were found to induce rate accelerations of 2 orders of magnitude over reactions catalyzed by HCl alone. We propose that the combination of strong mineral acids and chiral hydrogen-bond-donor catalysts may represent a general strategy for inducing enantioselectivity in reactions that require highly acidic conditions.
Assuntos
Álcoois/síntese química , Aldeídos/química , Alcenos/química , Ácido Clorídrico/química , Benzopiranos/síntese química , Catálise , Ciclização , Ligação de Hidrogênio , Quinina/análogos & derivados , Quinina/química , Estereoisomerismo , Tioureia/análogos & derivados , Ureia/análogos & derivadosRESUMO
We report a one-step catalytic, enantioselective method for the preparation of homoallylic N-Boc amines directly from acetals. Reactive iminium ion intermediates are generated in situ through the combination of an acetal, a chiral thiourea catalyst, trialkylsilyl triflate, and N-Boc carbamate and are subsequently trapped by a variety of allylsilane nucleophiles. No homoallylic ether byproducts are detected, consistent with allylation of the iminium intermediate being highly favored over allylation of the intermediate oxocarbenium ion. Acetals derived from aromatic aldehydes possessing a variety of functional groups and substitution patterns yield homoallylic amines with excellent levels of enantiomeric enrichment. Experimental and computational data are consistent with an anchoring hydrogen-bond interaction between the protioiminium ion and the amide of the catalyst in the enantiodetermining transition state, and with stereodifferentiation achieved through specific noncovalent interactions (NCIs) with the catalyst pyrenyl moiety. Evidence is provided that the key NCI in the major pathway is a π-stacking interaction, contrasting with the cation-π interactions invoked in previously studied reactions promoted by the same family of aryl-pyrrolidino-H-bond-donor catalysts.