RESUMO
BN-embedded nonacene, tridecacene, and heptadecacene frameworks were constructed using one-shot quadruple, sextuple, and octuple borylation reactions, respectively. The key to success is the judicious choice of borylating reagents and long-chain alkyl-substituted carbazolyl groups as boron-trapping groups, which suppressed the decrease in HOMO energy and insolubilization associated with borylation. Based on the product yields, each electrophilic C-H borylation proceeded in >99% yield, which is the best efficiency reported so far for C-H borylation reactions. Owing to the multiple resonance effects of boron and nitrogen, the prepared acenes exhibited ultra-narrowband green thermally activated delayed fluorescence with full-width at half-maximum of 12-16 nm; moreover, their kRISC values were in the order of 105 s-1. We fabricated an organic light-emitting diode by employing the nonacene as an emitter, which exhibited high external quantum efficiency (EQE) of 28.7%. The device also showed a minimum efficiency roll-off with an EQE of 25.8% at 1000 cd m-2.
RESUMO
Somatostatin receptors are members of G-protein coupled receptor superfamily. Receptors can be classified into five subtypes, SSTR1 to 5. The highly potent and orally active SSTR2 agonist 7, which had been identified by our group, was found out to have toxicological liabilities such as hERG inhibition and phospholipidosis (PLD). We investigated the relationship between in silico physicochemical properties and hERG and PLD, and explored well-balanced agonists to identify amide 19 and benzimidazole 30. As a result of this exploration, we found out that the value of (cLogP) [2] + (pKa) [2] needs to be less than 110 to mitigate the liabilities.
Assuntos
Amidas/farmacologia , Benzimidazóis/farmacologia , Desenho de Fármacos , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Fosfolipídeos/antagonistas & inibidores , Receptores de Somatostatina/agonistas , Amidas/síntese química , Amidas/química , Benzimidazóis/síntese química , Benzimidazóis/química , Relação Dose-Resposta a Droga , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Estrutura Molecular , Fosfolipídeos/metabolismo , Relação Estrutura-AtividadeRESUMO
Theoretical calculations of phosphorescent spectra and nonradiative transition (NRT) rate constants for S1 â T1, T1 â S0, and S1 â S0 were carried out to determine the best candidate for a blue-color phosphorescent complex among several derivatives of bis(2-phenylpyridine)(acetylacetonate)iridium(III). The geometries of the ground state (S0), the lowest triplet state (T1), and the lowest excited singlet state (S1) were optimized at the levels of density functional theory, in which B3LYP functionals and SBKJC+p basis sets were used. The NRT rate constants were derived by using a generating function method within the displaced harmonic oscillator model. The results of the calculation for phosphorescence showed that the introduction of F and/or CN substituents at the 4'/6'-th and 5'-th sites in 2-phenylpyridinate (ppy) ligands, respectively, causes a blue shift of the emission spectra. They also suggest that Ir(5-CN,6-F-ppy)2(acac), denoted 3(56) in the text, is a good candidate for a blue-color phosphorescent complex because a blue shift of emission spectra and a moderate intensity are obtained for phosphorescence and, furthermore, this complex is calculated to have a large rate constant for S1 â T1 and relatively smaller rate constants for T1 â S0 and S1 â S0 based on the calculations of spin-orbit coupling and nonadiabatic coupling constants.
RESUMO
The structure of the S1P2 antagonist 1 has been modified with the aim of improving its oral bioavailability. The chemical modification of the alkyl chain and carboxylic acid moieties of 1 led to significant improvements in the oral exposure of compounds belonging to this series. The optimization of the ring size of the urea portion of these molecules also led to remarkable improvements in the oral exposure. Based on these changes, the pyrrolidine derivative 16 was identified as a suitable candidate compound and showed excellent pharmacokinetic profiles in rat and dog, while maintaining high levels of potency and selective antagonistic activity toward S1P2.
Assuntos
Derivados de Benzeno/química , Receptores de Lisoesfingolipídeo/antagonistas & inibidores , Administração Oral , Animais , Derivados de Benzeno/síntese química , Derivados de Benzeno/farmacocinética , Disponibilidade Biológica , Cães , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Haplorrinos , Pirrolidinas/síntese química , Pirrolidinas/química , Pirrolidinas/farmacocinética , Ratos , Receptores de Lisoesfingolipídeo/metabolismo , Receptores de Esfingosina-1-Fosfato , Relação Estrutura-AtividadeRESUMO
Our initial lead compound 2 was modified to improve its metabolic stability. The resulting compound 5 showed excellent metabolic stability in rat and human liver microsomes. We subsequently designed and synthesized a hybrid compound of 5 and the 1,3-bis(aryloxy) benzene derivative 1, which was previously reported by our group to be an S1P2 antagonist. This hybridization reaction gave compound 9, which showed improved S1P2 antagonist activity and good metabolic stability. The subsequent introduction of a carboxylic acid moiety into 9 resulted in 14, which showed potent antagonist activity towards S1P2 with a much smaller species difference between human S1P2 and rat S1P2. Compound 14 also showed good metabolic stability and an improved safety profile compared with compound 9.
Assuntos
Derivados de Benzeno/farmacologia , Descoberta de Drogas , Receptores de Lisoesfingolipídeo/antagonistas & inibidores , Animais , Derivados de Benzeno/química , Derivados de Benzeno/metabolismo , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Ratos , Receptores de Lisoesfingolipídeo/metabolismo , Receptores de Esfingosina-1-Fosfato , Relação Estrutura-AtividadeRESUMO
The structure-activity relationships of a novel series of sphingosine-1-phosphate receptor antagonists have been examined in detail. The initial hit compound 1 was modified through synthesis to improve its S1P2 activity. The synthesis of a series of analogs revealed that 1,3-bis(aryloxy)benzene derivatives, as represented by 22, are potent and selective S1P2 antagonists.
Assuntos
Derivados de Benzeno/farmacologia , Descoberta de Drogas , Receptores de Lisoesfingolipídeo/antagonistas & inibidores , Derivados de Benzeno/síntese química , Derivados de Benzeno/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Receptores de Esfingosina-1-Fosfato , Relação Estrutura-AtividadeRESUMO
To identify structurally novel corticotropin-releasing factor 1 (CRF(1)) receptor antagonists, a series of bicyclic core analogs pyrrolo[1,2-b]pyridazines and pyrrolo[2,1-f]triazin-4(3H)-ones, which were designed based on a monocyclic core antagonist, was synthesized and evaluated. Among the compounds tested, 2-difluoromethoxy-4-methylpyridin-5-yl analog 27 was found to show efficacy in a dose-dependent manner in an elevated plus maze test in rats. The discovery process and structure-activity relationship is presented.
Assuntos
Ansiolíticos/química , Ansiolíticos/farmacologia , Piridazinas/química , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Triazinas/química , Triazinas/farmacologia , Animais , Ansiolíticos/síntese química , Ansiolíticos/farmacocinética , Masculino , Ligação Proteica/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Relação Estrutura-Atividade , Triazinas/síntese química , Triazinas/farmacocinéticaRESUMO
BACKGROUND: Pirarubicin (tetrahydropyranyl-adriamycin: THP) is a derivative of doxorubicin with reportedly less cardiotoxicity in adults. However no studies of cardiotoxicity in children treated with THP have been reported. This study was performed to assess the THP-induced cardiotoxicity for children with acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: This study comprised 61 asymptomatic patients aged from 7.6 to 25.7 years old. Median follow-up time after completion of anthracycline treatment was 8.1 years (range: 1.7-12.5). The cumulative dose of THP ranged from 120 to 740 mg/m(2) with a median of 180 mg/m(2) . Patients underwent electrocardiogram (ECG), echocardiography, the 6-min walk test (6MWT), and measurements of serum brain natriuretic peptide (BNP) before and after exercise. RESULTS: All subjects showed normal left ventricular function assessed by echocardiography. Ventricular premature contraction in Holter ECG and reduced exercise tolerance in the 6MWT were detected in 2/46 (3.3%) and 5/41(12.2%), respectively. Abnormal BNP levels were detected in 6/60 (10%) both before and after exercise. The cumulative dose of THP was significantly correlated with BNP levels after exercise (r = 0.27, P = 0.03), but not with any other cardiac measurements. Further analysis revealed that subjects with a high cumulative dose â§300 mg/m(2) had significantly higher BNP levels after exercise compared with subjects with a low cumulative dose <300 mg/m(2) (P = 0.04). CONCLUSIONS: No significant cardiac dysfunction was detected in long-term survivors who received THP treatment. The use of post-exercise BNP level to indicate high cardiotoxicity risk should be verified by further study.
Assuntos
Doxorrubicina/análogos & derivados , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Adulto , Antraciclinas/uso terapêutico , Antineoplásicos , Criança , Doxorrubicina/administração & dosagem , Doxorrubicina/toxicidade , Eletrocardiografia , Cardiopatias/induzido quimicamente , Testes de Função Cardíaca , Humanos , Sobreviventes , Adulto JovemRESUMO
OBJECTIVES/HYPOTHESIS: Occult lymph metastasis is an important prognosticator for the treatment of early oral tongue squamous cell carcinoma (SCC). The objective of this study was to evaluate the prognostic significance of tumor-infiltrating lymphocytes (TILs) in early oral tongue SCC. The combination of the TIL subtype and intermediate- or high-grade budding scores was investigated as a prognostic marker for occult neck metastases. STUDY DESIGN: Retrospective study. METHODS: Specimens from 62 patients with early oral tongue SCC treated with only primary surgery were analyzed by immunohistochemistry for CD4+, CD8+, FoxP3+, and CD45RO+ T cells and CD163+ macrophages. The highest number of each TIL subtype was counted in two areas of parenchyma and stroma in the tumor (Tumor) and peripheral stroma of the invasion margin. RESULTS: Based on multivariate analysis, a high density of Tumor CD163+ macrophages served as the poorest prognostic factor for regional control (RC) and disease-free survival (DFS). Patients with both a high density of Tumor CD163+ macrophages and an intermediate- or a high-grade budding score had a poor prognosis for RC according to the log-rank test. CONCLUSIONS: In summary, each TIL subtype may use different mechanisms during early and advanced stages of oral tongue SCC. A high density of Tumor CD163+ macrophages was determined to be a risk factor for RC and DFS as well as an additional stratification factor for RC in patients with intermediate- or high-grade budding scores. Therefore, identifying TIL subtypes in daily clinical practice can help determine a more successful and individualized therapeutic approach for early oral tongue SCC. LEVEL OF EVIDENCE: Step 4 (Level 4) Laryngoscope, 131:2512-2518, 2021.
Assuntos
Neoplasias de Cabeça e Pescoço/mortalidade , Linfócitos do Interstício Tumoral/imunologia , Recidiva Local de Neoplasia/epidemiologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Neoplasias da Língua/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Seguimentos , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/cirurgia , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Linfonodos/imunologia , Linfonodos/patologia , Metástase Linfática/imunologia , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/cirurgia , Língua/imunologia , Língua/patologia , Língua/cirurgia , Neoplasias da Língua/diagnóstico , Neoplasias da Língua/imunologia , Neoplasias da Língua/cirurgia , Microambiente Tumoral/imunologiaRESUMO
BACKGROUND: The majority of minimal residual disease (MRD)-positive patients with acute lymphoblastic leukemia (ALL) have poor outcomes. The ALL2000 study was performed to evaluate the efficacy of augmented chemotherapy based on MRD-restratification in childhood ALL. PROCEDURE: Between 2000 and 2004, 305 eligible patients with precursor B or T-cell ALL were enrolled in the ALL2000 study. The ALL941-based therapy protocol utilized PCR MRD assays using Immunoglobulin and T-cell receptor gene rearrangements. They were initially stratified into three risk-groups according to leukocyte count and age, and MRD levels were measured at weeks 5 (TP1) and 12 (TP2) for a second stratification. From week 14, patients with MRD levels ≥ 10(-3) received an increase in therapy (one risk group higher), while the remainder continued to receive the initial risk-adapted therapy. RESULTS: The overall 5-year event-free survival (EFS) rate for ALL2000 was 79.7 ± 2.4%. MRD stratification was feasible for 234 of 301 patients (77%) who achieved complete remission. The EFS rate of the MRD stratifiable (MRD) group was 82.5 ± 2.6%, considerably superior to the 74.7 ± 5.7% of MRD non-stratifiable (Non-MRD) group (P = 0.084) and the 74.4 ± 2.1% for ALL 941 (P = 0.012). MRD-positive patients at TP2 showed inferior outcomes as compared with MRD-negative cases, but the difference did not reach a statistically significant level in any risk groups or immunophenotypes. CONCLUSIONS: These results suggest that augmented therapy for MRD-positive patients at TP2 contributed to better outcomes of the ALL2000 study.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Masculino , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/classificação , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico , Fatores de Risco , Taxa de Sobrevida , Resultado do TratamentoRESUMO
The strain-promoted "double-click" (SPDC) reaction using Sondheimer diyne, a novel convergent method conjugating three molecules spontaneously, has enabled us to readily modify an azido-biomolecule with a small reporter azido-molecule.
Assuntos
Azidas/química , Carboidratos/química , Química Click/métodos , Corantes Fluorescentes/química , Lipídeos/química , Nucleotídeos/química , Proteínas/química , Linhagem Celular , Simulação por Computador , Cristalografia por Raios X , Humanos , Modelos Moleculares , Estrutura MolecularRESUMO
A number of epidemiological studies have implicated environmental chemicals including dioxins in the induction of negative effects on child development. To clarify the underlying mechanisms, almost all toxicologists have concentrated on effects on the offspring themselves. We examined an alternative hypothesis that gestational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a highly-toxic dioxin, targets factors related to maternal childcare to disturb offspring development. Oral administration of TCDD (1 µg/kg) to pregnant rats on gestational day 15 suppressed maternal licking behavior, a nursing behavior, and mammary gland maturation during the lactational stage, as well as the body weight and short-term memory of postnatal offspring. In support of these findings, maternal production of prolactin, a pituitary hormone essential for nursing including milk production, was decreased during the same period. Intracerebroventricular infusion of prolactin to dioxin-exposed dams restored or tended to restore many of the above defects observed both in mothers and offspring. The TCDD-dependent defects in maternal nursing behaviors can be due to a direct action on aryl hydrocarbon receptor (AHR) of lactating dams, because they did not emerge in AHR-knockout dams or control dams with TCDD-exposed offspring. Further examinations revealed that TCDD induces transforming growth factor ß1 expression, which suppresses prolactin-producing cell proliferation, in a nursing period-specific manner. In agreement with this, the number of prolactin-positive cells in nursing dams was decreased by TCDD. These results provide novel evidence that gestational dioxin exposure attenuates prolactin-stimulated nursing in lactating dams to impair offspring development, and that immaturity of prolactin-producing cells can contribute to them.
Assuntos
Poluentes Ambientais/toxicidade , Lactação/efeitos dos fármacos , Comportamento Materno/efeitos dos fármacos , Dibenzodioxinas Policloradas/toxicidade , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Prolactina/antagonistas & inibidores , Animais , Animais Recém-Nascidos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Peso ao Nascer/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Exposição Ambiental/efeitos adversos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Feminino , Feto , Expressão Gênica/efeitos dos fármacos , Idade Gestacional , Injeções Intraventriculares , Masculino , Memória de Curto Prazo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Prolactina/biossíntese , Prolactina/genética , Prolactina/farmacologia , Ratos , Ratos Wistar , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismoRESUMO
BACKGROUND: This study evaluated the combination of tumor budding and depth (BD model) and worst pattern of invasion (WPOI) as histopathological prognostic factors in clinical N0 early oral tongue carcinoma. METHODS: Data from 62 patients were retrospectively analyzed. Associations between histopathological factors (differentiation, stage, lymphatic invasion, blood vessel invasion, WPOI, and BD model) and regional control (RC) or disease-free survival (DFS) were evaluated. RESULTS: The five-year RC and DFS rates were 74% and 65%, respectively. Univariate analysis identified blood vessel invasion, lymphatic invasion, WPOI, and BD model, whereas multivariate analysis identified WPOI, and BD model, as predictive factors for RC. Univariate analysis identified lymphatic invasion, WPOI, and BD model, whereas multivariate analysis identified WPOI, as predictive factors for DFS. CONCLUSION: The pathological invasion patterns should be considered when determining the follow-up plan for patients with clinical N0 early oral tongue carcinoma.
Assuntos
Carcinoma de Células Escamosas , Neoplasias da Língua , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Humanos , Linfonodos/patologia , Linfonodos/cirurgia , Metástase Linfática , Invasividade Neoplásica/patologia , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Língua/patologia , Neoplasias da Língua/patologia , Neoplasias da Língua/cirurgiaRESUMO
Acromegaly is a disease caused by the oversecretion of growth hormone. It is currently treated by intravenous injection with cyclic peptide drugs that activate somatostatin receptor subtype 2 (SSTR2). Here, novel nonpeptidic, small-molecule, and orally active SSTR2 agonists were identified from a hit compound (13). Pharmacophore studies enabled scaffold hopping to obtain a unique 3,4,5-trisubstituted pyridine motif. Further optimization conferred potent SSTR2 agonistic activity and metabolic stability. Several compounds were evaluated and these showed good oral pharmacokinetic profiles in rats, and one representative compound (25) showed highly potent inhibition of growth hormone secretion induced by growth hormone-releasing hormone in rats. Based on these results, 25 was identified as a promising lead for further optimization. A structure-activity relationship (SAR) study and the metabolic stability data for this compound are also described.
Assuntos
Acromegalia , Acromegalia/tratamento farmacológico , Animais , Hormônio do Crescimento , Ratos , Receptores de Somatostatina/agonistas , Somatostatina , Relação Estrutura-AtividadeRESUMO
Work function changes, or vacuum-level shifts (ΔVLS), in Al(001) surfaces by the adsorption of thin layers composed of tris(8-hydroxyquinolinato)aluminum (Alq3) and/or LiF are theoretically investigated. First-principles calculations reasonably reproduce experimentally obtained ΔVLS values, enabling us to discuss the underlying mechanism. Dipole moment of Alq3 and interfacial charge rearrangement (Pauli push-back effect) are the main reasons for ΔVLS at Al(001)-Alq3 and Al(001)-LiF interfaces, respectively. For a stacked Al(001)-LiF-Alq3 layer configuration, theory suggests a more complicated picture, which takes charge rearrangement between LiF and Alq3 layers into account, than a simple sum rule of dipole contributions from the two layers.
RESUMO
Introduction of an amino group at the para position of doubly sterically-hindered aryl azides significantly enhances the reactivity with cyclooctynes. The distortability of the azido group is synergistically enhanced by the para-electron-donating group and two bulky ortho substituents, which increases the HOMO energy level and provoke the steric inhibition of resonance, respectively.
RESUMO
A diphenylanthracene dimethylamine derivative (9-{3,5-di( N, N-dimethylaminoethoxy)phenyl}-10-phenyl-anthracene, DPAMA) was synthesized by the Suzuki-Miyaura cross-coupling reaction. Its ammonium salt, 9-{3,5-di(trimethylammonium ethoxy)phenyl}-10-phenyl-anthracene dichloride (DPAMA-Cl), was also synthesized as a reference material. DPAMA was characterized by UV-vis and fluorescence spectroscopy, cyclic voltammetry, photoelectron yield spectroscopy, and X-ray photoelectron spectroscopy to evaluate the work function-modifying ability of DPAMA on indium tin oxide (ITO) and ZnO. The work functions of ITO and ZnO changed from 4.4 and 4.0 eV (pristine) to 3.8 and 3.9 eV, respectively. Using this surface modification effect of DPAMA, inverted organic light-emitting diodes were fabricated with device structures of ITO/DPAMA/Alq3/NPD/MoO3/Al (Alq3 = tris(8-hydroxyquinolinato)aluminum; NPD = N, N'-di-[(1-naphthyl)- N, N'-diphenyl]-1,1'-(biphenyl)-4,4'-diamine) and ITO/ZnO/DPAMA/Alq3/NPD/MoO3/Al. Both devices showed good performance at the range of current density, 1-300 mA/cm2. The best inverted organic light-emitting diodes device showed luminance of 7720 cd/m2, current efficiency of 4.51 cd/A, and external quantum efficiency of 1.45%. Also, poly(3-hexylthiophene):mixed phenyl-C61 and C71 butyric acid methyl ester-based organic solar cells using DPAMA and DPAMA-Cl as electron-transporting materials showed power conversion efficiencies of 3.3 and 3.4%, respectively.
RESUMO
In clinical N0 early oral tongue carcinoma, treatment of occult lymph node metastasis is controversial. The purpose of this study was to assess the histopathological risk factors for predicting late lymph node metastasis in early oral tongue carcinoma. We retrospectively reviewed 48 patients with early oral tongue squamous cell carcinoma. Associations between the histopathological factors (depth of tumor, differentiation, blood vessel invasion, lymphatic invasion, and tumor budding) and late lymph metastasis were analyzed. Although the univariate analysis identified blood vessel invasion, lymphatic invasion, and high-grade tumor budding as predictive factors for neck recurrence (p < 0.001), the Cox proportional hazards model identified high-grade tumor budding as an independent predictive factor (p < 0.01). The combination of a tumor depth ≥ 3 mm and high-grade tumor budding yielded high diagnostic accuracy. Tumor depth and budding grade were identified as histopathological risk factors for late neck recurrence in clinical N0 early oral tongue carcinoma.
Assuntos
Carcinoma de Células Escamosas/patologia , Metástase Linfática/patologia , Neoplasias da Língua/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/mortalidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Fatores de Risco , Neoplasias da Língua/mortalidadeRESUMO
Thiazolobenzyne, which is a benzyne species fused with a thiazole ring, was efficiently generated via an iodine-magnesium exchange reaction of an ortho-iodoaryl triflate-type precursor using a trimethylsilylmethyl Grignard reagent as an activator. A wide range of arynophiles reacted efficiently with the thiazolobenzynes generated by this method to afford various multisubstituted benzothiazoles.
RESUMO
The structures and intermolecular interaction energies of 10 dimers, included in the mesogenic core structures of typical liquid crystalline (LC) compounds, are obtained at the MP2/6-31G(d) level of theory. It is proved that the dispersion energy significantly contributes to the total interaction energy of these dimers. Even when bulky substituents are introduced into the core part, the interaction energy is still large. It is also revealed that when a long intermolecular distance is provided by a high steric repulsion originating from the linkage of two phenyl groups, the dispersion energy is significantly small. However, in this range of intermolecular distances, the electrostatic energy caused by a strong quadrupole-quadrupole attractive interaction plays a dominant role, and as a result, a rather stable dimer is formed. In all 10 dimers, the dispersion, electrostatic, and exchange-repulsion energies strongly depend on the geometrical orientation of the molecules. The calculated interaction energies of these dimers are also compared with the corresponding experimentally measured viscosities. The results suggest an explicit linear relationship between the interaction energies and viscosities.