RESUMEN
Herein, atropisomeric 8-aryltetrahydroisoquinolines have been synthesized and biologically evaluated. Based on our structure-activity relationship study, a highly bioactive racemic compound has been produced, and it exhibited high antiproliferative activities against various cancer cell lines, including docetaxel-resistant breast cancer cell lines. Each enantiomer can be synthesized in an enantioselective manner by employing the chiral phosphoric acid-catalyzed atroposelective Pictet-Spengler cyclization. An axially (R)-configured enantiomer showed a higher biological activity compared with the axially (S)-configured enantiomer. Further biological studies suggested that the (R)-enantiomer overcomes docetaxel resistance via the downregulation of signal transducer and activator of transcription 3 activation and consequently induces cellular apoptosis in docetaxel-resistant triple-negative breast cancer cell lines.
Asunto(s)
Tetrahidroisoquinolinas , Neoplasias de la Mama Triple Negativas , Humanos , Docetaxel/farmacología , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/metabolismo , Apoptosis , Línea Celular TumoralRESUMEN
An unprecedented example of a chiral phosphoric acid-catalyzed atroposelective Pictet-Spengler reaction of N-arylindoles is reported. Highly enantioenriched N-aryl-tetrahydro-ß-carbolines with C-N bond axial chirality are obtained via dynamic kinetic resolution. The hydrogen bond donor introduced on the bottom aromatic ring, forming a secondary interaction with the phosphoryl oxygen, is essential to achieving high enantioselectivity. A wide variety of substituents are tolerable with this transformation to provide up to 98 % ee. The application of electron-withdrawing group-substituted benzaldehydes enables the control of both axial and point stereogenicity. Biological evaluation of this new and unique scaffold shows promising antiproliferative activity and emphasizes the significance of atroposelective synthesis.
Asunto(s)
Antineoplásicos/química , Ácidos Fosfóricos/química , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Benzaldehídos/química , Carbolinas/química , Carbono/química , Catálisis , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Enlace de Hidrógeno , Nitrógeno/química , EstereoisomerismoRESUMEN
BACKGROUND: To evaluate the relationship between biochemical recurrence and post-radiation prostate-specific antigen (PSA) kinetics in patients with localized prostate cancer treated by radiotherapy with various durations of androgen deprivation therapy (ADT). METHODS: We reviewed our single-institution, retrospectively maintained data of 144 patients with T1c-T3N0M0 prostate cancer who underwent three-dimensional conformal radiotherapy (3D-CRT) between December 2005 and December 2015 and 113 patients were fulfilled the inclusion criteria. In this cohort, 3D-CRT was delivered with a dose in the range from 70.0 to 72.0 Gy with ADT. All patients received ADT as concurrent regimens. Biochemical recurrence was defined on the basis of the following: "PSA nadir + 2.0 ng/ml or the clinical judgement of attending physicians". Kaplan-Meier, log-rank, and Cox regression analyses were carried out. RESULTS: The median follow-up period was 54.0 months. The median duration of ADT was 17 months (interquartile range, 10-24 months). There was a trend toward statistical significant correlation between post-radiation PSA decline rate of ≥ 90% and PSA recurrence (p = 0.056). The same correlation could be observed in D'Amico high-risk patients (p = 0.036). However, it was not observed between PSA nadir and PSA recurrence (p = 0.40) in univariate analysis. Furthermore, multivariate analysis showed that post-radiation PSA decline rate of ≥ 90% was a significant predictor of biochemical recurrence in patients who received radiotherapy with various durations of ADT (p = 0.044). CONCLUSIONS: Post-radiation PSA decline rate of ≥ 90% was a prognostic factor for biochemical recurrence in localized prostate cancer patients received 3D-CRT with various durations of ADT.
Asunto(s)
Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/radioterapia , Radioterapia Conformacional/métodos , Anciano , Antagonistas de Andrógenos/uso terapéutico , Estudios de Cohortes , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Masculino , Recurrencia Local de Neoplasia/sangre , Recurrencia Local de Neoplasia/patología , Neoplasias de la Próstata/metabolismo , Estudios RetrospectivosRESUMEN
Purpose: To evaluate whether the image quality of chest radiographs obtained using a camera-type portable X-ray device is appropriate for clinical practice by comparing them with traditional mobile digital X-ray devices. Materials and Methods: Eighty-six patients who visited our emergency department and underwent endotracheal intubation, central venous catheterization, or nasogastric tube insertion were included in the study. Two radiologists scored images captured with traditional mobile devices before insertion and those captured with camera-type devices after insertion. Identification of the inserted instruments was evaluated on a 5-point scale, and the overall image quality was evaluated on a total of 20 points scale. Results: The identification score of the instruments was 4.67 ± 0.71. The overall image quality score was 19.70 ± 0.72 and 15.02 ± 3.31 (p < 0.001) for the mobile and camera-type devices, respectively. The scores of the camera-type device were significantly lower than those of the mobile device in terms of the detailed items of respiratory motion artifacts, trachea and bronchus, pulmonary vessels, posterior cardiac blood vessels, thoracic intervertebral disc space, subdiaphragmatic vessels, and diaphragm (p = 0.013 for the item of diaphragm, p < 0.001 for the other detailed items). Conclusion: Although caution is required for general diagnostic purposes as image quality degrades, a camera-type device can be used to evaluate the inserted instruments in chest radiographs.
RESUMEN
Chemically modified proteins have diverse applications; however, conventional chemo-selective methods often yield heterogeneously labeled products. To address this limitation, site-specific protein labeling holds significant potential, driving extensive research in this area. Nevertheless, site-specific modification of native proteins remains challenging owing to the complexity of their functional groups. Therefore, a method for site-selective labeling of intact proteins is aimed to design. In this study, a novel approach to traceless affinity-directed intact protein labeling is established, which leverages small binding proteins and genetic code expansion technology. By applying this method, a site-specific antibody labeling with a drug, which leads to the production of highly effective antibody-drug conjugates specifically targeting breast cancer cell lines is achieved. This approach enables traceless conjugation of intact target proteins, which is a critical advantage in pharmaceutical applications. Furthermore, small helical binding proteins can be easily engineered for various target proteins, thereby expanding their potential applications in diverse fields. This innovative approach represents a significant advancement in site-specific modification of native proteins, including antibodies. It also bears immense potential for facilitating the development of therapeutic agents for various diseases.
Asunto(s)
Inmunoconjugados , Proteínas/metabolismo , AnticuerposRESUMEN
Palladium-catalyzed asymmetric allylic alkylation has proven to be a powerful method for the preparation of a wide variety of chiral molecules. However, the catalytic and atroposelective allylic alkylation is still rare and challenging, especially for biaryl substrates. Herein, we report the palladium-catalyzed desymmetric and atroposelective allylation, in which the palladium complex with a chiral phosphoramidite ligand enables desymmetrization of nucleophilic 2-arylresorcinols in a highly enantioselective manner. With the aid of the secondary kinetic resolution effect, a wide variety of substrates containing a hydroxymethyl group at the bottom aromatic ring are able to provide O-allylated products up to 98:2 er. Computational studies show an accessible quadrant of the allylpalladium complex and provide three plausible transition states with intra- or intermolecular hydrogen bonding. The energetically favorable transition state is in good agreement with the observed enantioselectivity and suggests that the catalytic reaction would proceed with an intramolecular hydrogen bond.
RESUMEN
The dissolution behavior of magnetite deposited on flow mini-channel surfaces within a printed circuit heat exchanger (PCHE) and the corrosion behavior of a STS 316L PCHE material were investigated in an ethylendiaminetetraacetic acid (EDTA)-based chemical cleaning solution at 93 °C. The fouling in the PCHE was simulated using a water-steam circulation loop system. Most of the magnetite deposits were rapidly dissolved in the early stage of the circulation chemical cleaning. An empirical equation for estimating the dissolution percentage was derived as a function of cleaning time. The PCHE material showed excellent corrosion resistance during the chemical cleaning tests. These results indicate the fouling layers in the PCHEs can be removed efficiently by the chemical cleaning process without concern about base metal corrosion.