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BACKGROUND: Using the transverse sinus as a conduit to treat a transverse sigmoid sinus dural arteriovenous fistula is uncommon. This report describes a minimally invasive direct puncture technique for the transverse sinus to treat a complex dural arteriovenous fistula in a hybrid operating room. CASE: The patient was a 64-year-old man with intractable status epilepticus. Digital subtraction angiography demonstrated a right transverse sigmoid sinus dural arteriovenous fistula (Borden type II, Cognard type IIa+b). We performed a transcranial direct puncture because the femoral vein approach was not feasible due to bilateral thrombosed sinuses. Under general anesthesia and park-bench patient positioning, the transverse sinus was exposed and catheterized, and the affected sinus was embolized using microcoils. The fistula was completely obliterated, resolving the status epilepticus. CONCLUSIONS: Direct puncture of the transverse sinus can be effective for treating a transverse sigmoid sinus dural arteriovenous fistula. In a hybrid operating room, combined treatments can be performed comfortably and safely in a single session of general anesthesia. This treatment option is a viable alternative when other methods are unsuccessful.
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cis,cis-Muconate (ccMA) is a promising platform for use in synthesizing various polymers. A glucose-free ccMA production using Pseudomonas sp. NGC7 from hardwood lignin-derived aromatic compounds was previously reported. In that system, syringyl nucleus compounds were essential for growth. Here, it is shown that NGC7 is available for glucose-free ccMA production even from a mixture of lignin-derived aromatics that does not contain syringyl nucleus compounds. By introducing a gene set for the protocatechuate (PCA)-shunt consisting of PCA 3,4-dioxygenase and PCA decarboxylase into an NGC7-derived strain deficient in PCA 3,4-dioxygenase and ccMA cycloisomerase, it was succeeded in constructing a ccMA-producing strain that grows on a lignin-derived aromatics mixture containing no syringyl nucleus compounds. Finally, it is demonstrated that the engineered strain produced ccMA from sugar cane bagasse alkaline extract in 18.7 mol%. NGC7 is thus shown to be a promising microbial chassis for biochemicals production from lignin-derived aromatics.
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Dioxigenasas , Pseudomonas , Saccharum , Proteínas Bacterianas , Celulosa , Glucosa , Lignina/química , Ingeniería Metabólica/métodos , Pseudomonas/genética , Saccharum/química , Ácido Sórbico/análogos & derivados , Ácido Sórbico/metabolismoRESUMEN
PURPOSE: We developed a navigation system that superimposes the fractional anisotropy (FA) color map of pre-operative diffusion tensor imaging (DTI) and intraoperative magnetic resonance imaging (MRI). The current study aimed to investigate the usefulness of this system for neurophysiological monitoring and examination under awake craniotomy during tumor removal. METHOD: A total of 10 glioma patients (4 patients with right-side tumors; 5 men and 5 women; average age, 34 years) were evaluated. Among them, the tumor was localized to the frontal lobe, insular cortex, and parietal lobe in 8, 1, and 1 patient, respectively. There were 3 patients who underwent surgery on general anesthesia, while 7 patients underwent awake craniotomy. The index of DTI anisotropy taken pre-operatively (magnetic field: 3 tesla, 6 motion probing gradient directions) was analyzed as a color map (FA color map) and concurrently co-registered in the intraoperative MRI within the navigation. In addition to localization of the bipolar coagulator and the cortical stimulator for brain mapping on intraoperative MRI, the pre-operative FA color map was also concurrently integrated and displayed on the navigation monitor. This white matter nerve functional information was confirmed directly by using neurological examination and referring to the electrophysiological monitoring. RESULTS: Intraoperative MRI, integrated pre-operative FA color map, and microscopic surgical view were displayed on one screen in all 10 patients, and white matter fibers including the pyramidal tract were displayed as a reference in blue. Regarding motor function, motor-evoked potential was monitored as appropriate in all cases, and removal was possible while directly confirming motor symptoms under awake craniotomy. Furthermore, the white matter fibers including the superior longitudinal fasciculus were displayed in green. Importantly, it was useful not only to localize the resection site, but to identify language-related, eye movement-related, and motor fibers at the electrical stimulation site. All motor and/or language white matter tracts were identified and visualized with the co-registration and then with an acceptable post-operative neurological outcome. CONCLUSION: Co-registering an intraoperative MR images and a pre-operative FA color map is a practical and useful method to predict the localization of critical white matter nerve functions intraoperatively in glioma surgery.
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BACKGROUND: Eagle syndrome, or elongated styloid process syndrome, is a rare cause of cerebral infarction. When the styloid process is elongated but the internal carotid artery (ICA) is morphologically normal on three-dimensional computed tomography angiography (3D-CTA), determining the causal relationship between elongation and cerebral infarction is difficult. OBSERVATIONS: The patient was a 27-year-old man who experienced two left cerebral infarctions in 3 months. On 3D-CTA, the styloid process was elongated, but the structure of the ICA was normal. When the patient's neck was rotated leftward, the peak systolic velocity and pulsatility index increased (shown via dynamic subtraction ultrasonography) and ICA stenosis was evident (shown via subtraction angiography). The styloid process was removed, and the cerebral infarction did not recur in the 2 years after surgery. LESSONS: This is the first report to document that indirect compression of ICA by the styloid process can cause Eagle syndrome. The blood flow changes of the ICA on dynamic ultrasonography revealed morphological changes that were hidden on 3D-CTA or nondynamic subtraction angiography.
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Surgical treatments for moyamoya disease (MMD) include direct revascularization procedures with proven efficacy, for example, superficial temporal artery (STA) to middle cerebral artery (MCA) bypass, STA to anterior cerebral artery bypass, occipital artery (OA) to MCA bypass, or OA to posterior cerebral artery bypass. In cases with poor development of the parietal branch of the STA, the posterior auricular artery (PAA) is often developed and can be used as the bypass donor artery. In this report, the authors describe double direct bypass performed using only the PAA as the donor in the initial surgery for MMD.In the authors' institution, MMD is routinely treated with an STA-MCA double bypass. Some patients, however, have poor STA development, and in these cases the PAA is used as the donor artery. The authors report the use of the PAA in the treatment of 4 MMD patients at their institution from 2013 to 2016. In all 4 cases, a double direct bypass was performed, with transposition of the PAA as the donor artery. Good patency was confirmed in all cases via intraoperative indocyanine green angiography and postoperative MRA or cerebral angiography. The mean blood flow measurement during surgery was 58 ml/min. No patients suffered a stroke after revascularization surgery.
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A novel, optically active, cis-transoidal poly(phenylacetylene) bearing an L-proline residue as the pendant group (poly-1) was prepared by the polymerization of the corresponding monomer using a rhodium catalyst in water, and its chiroptical property was investigated using circular dichroism spectroscopy. Poly-1 showed intense Cotton effects in the UV-visible region of the polymer backbone in water, resulting from the prevailing one-handed helical conformation induced by the covalent-bonded chiral L-proline pendants and exhibited a unique helix-sense inversion in response to external, achiral, and chiral stimuli, such as the solvent and interactions with chiral small molecules. We found that poly-1 could enantioselectively trap 1,1'-2-binaphthol within its hydrophobic helical cavity inside the polymer in aqueous media and underwent an inversion of its helical sense in the presence of one of the enantiomers. The effect of the optical purity of 1,1'-2-binaphthol on the chiroptical properties of poly-1 was also investigated.
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Acetileno/análogos & derivados , Prolina/química , Acetileno/química , Catálisis , Dicroismo Circular/métodos , Furanos/química , Interacciones Hidrofóbicas e Hidrofílicas , Conformación Molecular , Polímeros/química , Rodio/química , Solventes/química , Espectrofotometría Ultravioleta/métodos , Estereoisomerismo , Tolueno/química , Agua/químicaRESUMEN
To establish objective criteria for "grade 3" (G3) in T1 (TNM staging) colorectal cancer (CRC), a total of 296 T1 CRC cases were reviewed. The incidence of nodal involvement differed most greatly between G3 and non-G3 (21/27 [27%] and 6/162 [3.7%], respectively; P < .0001), when G3 was applied to tumors containing either or both of the following: (1) 10 or more solid cancer nests in the microscopic field of a 4x objective lens and (2) a mucin-producing component fully occupied the microscopic field of a 40x objective lens. Regarding G3, vascular invasion, and tumor budding as indicating the risk of metastasis, nodal involvement rate was 21.0% in the tumors with 1 or more risk factors, whereas it was only 1.7% in the no-risk tumors (P < .0001). In patients treated with local excision only, nodal recurrence occurred in 3 (20%) of 15 risk-positive patients, whereas none of 42 patients without risk factors had nodal recurrence (P = .016). In cases of locally excised T1 CRC, G3 as determined by the proposed criteria, vascular invasion, and budding would comprise a useful combination of parameters for determining the indication for additional laparotomy.
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Neoplasias Colorrectales/clasificación , Neoplasias Colorrectales/patología , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Colorrectales/metabolismo , Femenino , Humanos , Metástasis Linfática/patología , Masculino , Persona de Mediana Edad , Mucinas/metabolismo , Estadificación de Neoplasias , PronósticoRESUMEN
In this article, we report crystal structures for inhibitor-kinase complexes in which the inhibitor has different binding orientations and hydrogen-bonding patterns with extracellular-signal regulated kinase 2 and insulin receptor tyrosine kinase. Our crystallographic studies, and sequence and structural analyses of 532 coordinates of kinases held in the Protein Data Bank, suggest that the length of the "specificity linker" described here is a key structural element of the hydrogen-bonding patterns between protein kinases and their inhibitors.
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Proteína Quinasa 1 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 1 Activada por Mitógenos/química , Inhibidores de Proteínas Quinasas/química , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/química , Adenosina Trifosfato , Cristalografía por Rayos X , Bases de Datos de Proteínas , Humanos , Enlace de Hidrógeno , Análisis de Secuencia de ProteínaRESUMEN
PURPOSE: This study was designed to investigate the pathophysiology of posterior complex fistula with reference to pelvic anatomy. METHODS: Three hundred twenty posterior complex fistula patients, operated on between 1995 and 2004, were examined. Thirty patients underwent preoperative magnetic resonance imaging. We also conducted two cadaver dissections. Posterior complex fistulas were classified by the extension forms of secondary ducts. RESULTS: The septum of the ischiorectal fossa, which comprises membranes between Alcock's canal and the anal canal, was newly identified intraoperatively and confirmed by magnetic resonance imaging and dissection. The ischiorectal fossa was separated by the septum of the ischiorectal fossa; the upper portion was the inferior levator space, and the lower was the clinical ischiorectal space. Primary lesions were found mainly in the posterior deep space (the anterior border was the internal sphincter, the superior border was the inferior surface of the puborectalis, the inferior and lateral borders were the anterior surfaces of the external sphincter; 97 percent). The primary opening was located in a posterior anal crypt (96 percent). The prevalence of posterior complex fistula limited to the posterior deep space, extending to the inferior levator space, the clinical ischiorectal space, or both, were 21, 14, 53, and 12 percent, respectively. The primary duct from a crypt proceeds diagonally into the internal sphincter to the posterior deep space. The posterior deep space is adjacent to the clinical ischiorectal space and the inferior levator space bordering on the external sphincter. If an abscess penetrates the sphincter from the posterior deep space, it can reach the clinical ischiorectal space and/or the inferior levator space. CONCLUSIONS: Recognition of the posterior deep space, the septum of the ischiorectal fossa, the inferior levator space, and the clinical ischiorectal space may be crucial for effective surgical management of posterior complex fistula.
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Fístula Rectal/cirugía , Adulto , Anciano , Cadáver , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Fístula Rectal/patología , Recto/anatomía & histología , Resultado del TratamientoRESUMEN
We generated recombinant artificial extracellular matrix (ECM) proteins containing repetitive Arg-Gly-Asp (RGD) sequences: double (RGD2), 21 (RGD21) and 43 (RGD43) repeats of RGD. RGD43-coated glass slides promoted fibroblast NIH3T3 cell adhesion and spreading on the surface. Since actin stress fibers and focal contacts were also observed in cells adhering on RGD43-coated glass slides, it was suggested that the RGD peptides in RGD43 transmitted an adhesion signal via integrins and promoted cell adhesion. We coated recombinant ECM proteins, each containing repetitive RGD domains, on polystyrene plates and investigated the effects of RGD length on the cell adhesion ability using three different cell lines, namely, fibroblast NIH3T3, HeLa cancer and neuronal PC12 cell lines. The results indicated that RGD43 had a cell adhesion ability superior to those of natural extracellular matrix proteins, fibronectin and laminin, although the effects of RGD repeat length on the cell adhesion ability depended on the cell line. As an artificial three-dimensional scaffold for cell cultivation, we also prepared an RGD43 hydrogel by a cross-linking reaction using glutaraldehyde. On the RGD43 hydrogel scaffold, fibroblast cells also successfully adhered under serum-free conditions.
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Adhesión Celular/fisiología , Técnicas de Cultivo de Célula/métodos , Proteínas de la Matriz Extracelular/metabolismo , Oligopéptidos/química , Oligopéptidos/metabolismo , Ingeniería de Tejidos/métodos , Animales , Materiales Biomiméticos/química , Materiales Biomiméticos/metabolismo , Materiales Biocompatibles Revestidos/química , Proteínas de la Matriz Extracelular/química , Células HeLa , Humanos , Ratones , Células 3T3 NIH , Células PC12 , RatasRESUMEN
Using overlap elongation PCR, we created repetitive DNA libraries encoding the elastin VPGVG and collagen-like GERGDRGDP sequences. From these libraries we isolated two repetitive DNA sequences, Col-5 encoding [(GERGDRGDP)(5)GER], and Ela-16 encoding [(VPGVG)(16)VPG]. Both proteins were expressed as thioredoxin fusion proteins. The resulting recombinant extracellular matrix-like proteins had the expected properties (cell adhesive ability and thermally responsive structural change) of the functional motif sequence unit used.
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Biotecnología/métodos , Colágeno/química , Elastina/química , Matriz Extracelular/metabolismo , Proteínas Recombinantes/química , Secuencias de Aminoácidos , Animales , Secuencia de Bases , Adhesión Celular , ADN/química , Electroforesis en Gel de Agar , Electroforesis en Gel de Poliacrilamida , Biblioteca de Genes , Calor , Ratones , Datos de Secuencia Molecular , Células 3T3 NIH , Oligonucleótidos/química , Reacción en Cadena de la Polimerasa , Análisis de Secuencia de ADN , Temperatura , Tiorredoxinas/químicaRESUMEN
In a previous study, we described the structure-activity relationships (SARs) for a series of thiazolidenebenzenesulfonamide derivatives. These compounds were found to be highly potent inhibitors of the wild type (WT) and Y181C mutant reverse transcriptases (RTs) and modest inhibitors of K103N RT. These molecules are thus considered to be a novel class of non-nucleoside HIV-1 RT inhibitors (NNRTIs). In this paper, we have examined the effects of substituents on both the thiazolidene and benzenesulfonamide moieties. Introduction of a 2-cyanophenyl ring into these moieties significantly enhanced anti-HIV-1 activity, whereas a 2-hydroxyphenyl group endowed potent activity against RTs, including K103N and Y181C mutants. Among the series of molecules examined, 10l and 18b (YM-228855), combinations of 2-cyanophenyl and 4-methyl-5-isopropylthiazole moieties, showed extremely potent anti-HIV-1 activity. The EC50 values of 101 and 18b were 0.0017 and 0.0018 microM, respectively. These values were lower than that of efavirenz (3). Compound 11g (YM-215389), a combination of 2-hydroxyphenyl and 4-chloro-5-isopropylthiazole moieties, proved to be the most active against both K103N and Y181C RTs with IC50 values of 0.043 and 0.013 microM, respectively.
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Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/farmacología , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , Línea Celular , VIH-1/efectos de los fármacos , Humanos , Espectroscopía de Resonancia Magnética , Pruebas de Sensibilidad Microbiana , Inhibidores de la Transcriptasa Inversa/química , Espectrometría de Masa Bombardeada por Átomos Veloces , Relación Estructura-Actividad , Sulfonamidas/químicaRESUMEN
We demonstrate the elongation of various hexanucleotide sequences with thermophilic DNA polymerase, under isothermal or thermal cyclic reaction conditions. We prepared 10 types of double repeat hexanucleotide duplexes with various GC compositions containing between 0 and 6 GC nucleotides per repeat and incubated these duplexes with thermophilic Taq DNA polymerase and dNTPs at various temperatures. All of the model repetitive short duplexes were elongated under the isothermal incubation conditions, although there were some differences in the elongation efficiencies derived from the GC composition in the repetitive sequences. It was also found that all of the model repetitive duplexes were extended more effectively by a 3-step thermal cyclic reaction involving denaturation, annealing, and extension. On the basis of this technique, we prepared a glutamate-encoding short repetitive duplex and created long repetitive DNAs under isothermal and thermal cyclic reaction conditions. DNA sequencing analysis of the cloned repetitive DNA revealed that well-ordered long repetitive DNAs of various chain lengths were created by this DNA polymerase-catalyzed ligation method, and these were easily cloned into vectors by the TA-cloning method. This method could be useful for obtaining DNAs encoding arbitrary long repetitive amino acid sequences more effectively than the conventional T4 ligase-catalyzed ligation method.
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ADN Polimerasa Dirigida por ADN/química , Secuencia Rica en GC , Biblioteca de Genes , Nucleótidos/química , Oligonucleótidos/química , Secuencias Repetitivas de Ácidos Nucleicos , Catálisis , ADN/química , TemperaturaRESUMEN
A random high-throughput screening (HTS) program to discover novel nonnucleoside reverse transcriptase inhibitors (NNRTIs) has been carried out with MT-4 cells against a nevirapine-resistant virus, HIV-1(IIIB-R). The primary hit, a thiazolidenebenzenesulfonamide derivative, possessed good activity. A systematic modification program examining various substituents at the 3-, 4-, and 5-positions on the thiazole ring afforded compounds with enhanced anti-HIV-1 and reverse transcriptase (RT) inhibitory activities. These results confirm the important role of the substituents at these positions and the thiazolidenebenzenesulfonamide motif as a valuable lead series for the next generation NNRTIs.
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Transcriptasa Inversa del VIH/antagonistas & inhibidores , Inhibidores de la Transcriptasa Inversa/síntesis química , Sulfonamidas/síntesis química , Bencenosulfonatos , Sitios de Unión , Farmacorresistencia Viral , VIH-1/efectos de los fármacos , Estructura Molecular , Nevirapina , Unión Proteica , Inhibidores de la Transcriptasa Inversa/farmacología , Relación Estructura-Actividad , Sulfonamidas/farmacología , Tiazoles , Replicación Viral/efectos de los fármacosRESUMEN
We developed a novel method for creating repetitive DNA libraries using overlap elongation PCR, and prepared a DNA library encoding repetitive Arg-Gly-Asp (RGD) cell adhesive motifs. We obtained various length DNAs encoding repetitive RGD from a short monomer DNA (18 bp) after a thermal cyclic reaction without a DNA template for amplification, and isolated DNAs encoding 2, 21, and 43 repeats of the RGD motif. We cloned these DNAs into a protein expression vector and overexpressed them as thioredoxin fusion proteins: RGD2, RGD21, and RGD43, respectively. The solubility of RGD43 in water was low and it formed a fibrous precipitate in water. Scanning electron microscopy revealed that RGD43 formed a branched 3D-network structure in the solid state. To evaluate the function of the cell adhesive motifs in RGD43, mouse fibroblast cells were cultivated on the RGD43 scaffold. The fibroblast cells adhered to the RGD43 scaffold and extended long filopodia.
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Oligopéptidos/genética , Proteínas Recombinantes de Fusión/genética , Secuencias de Aminoácidos , Animales , Secuencia de Bases , Adhesión Celular/genética , Línea Celular , Cartilla de ADN/genética , ADN Recombinante/genética , Escherichia coli/genética , Expresión Génica , Biblioteca de Genes , Ratones , Microscopía Electrónica de Rastreo , Células 3T3 NIH , Reacción en Cadena de la Polimerasa , Proteínas Recombinantes de Fusión/aislamiento & purificación , Proteínas Recombinantes de Fusión/ultraestructura , Secuencias Repetitivas de AminoácidoRESUMEN
BACKGROUND & AIMS: Various histologic findings exist for managing patients with malignant polyps. Our goal was to determine the criteria for a conservative approach to patients with locally excised early invasive carcinoma. METHODS: In 292 early invasive tumors (local resection followed by laparotomy [80 tumors, group A], local resection only [41 tumors, group B], and primarily laparotomy [171 tumors, group C], potential parameters for nodal involvement were analyzed. The status of the endoscopic resection margin also was examined for the risk for intramural residual tumor. RESULTS: Unfavorable tumor grade, definite vascular invasion, and tumor budding were the combination of qualitative factors that most effectively discriminated the risk for nodal involvement in patients in groups A-C. The nodal involvement rate was 0.7%, 20.7%, and 36.4% in the no-risk, single-risk, and multiple-risks group, respectively. Thirty-two and 9 patients from group B were assigned to the no-risk and one-risk group, respectively; extramural recurrence occurred in 2 patients with risk factors. Considering quantitative risk parameters for submucosal invasion (i.e., width > or =4000 microm or depth > or =2000 microm), nodal involvement (including micrometastases) was not observed in the redefined no-risk group that accounted for about 25% of the patients from groups A and C. An insufficiency of endoscopic resection could be evaluated most precisely based on the coagulation-involving tumor, rather than the 1-mm rule for the resection margin. CONCLUSIONS: Provided that the criterion of sufficient excision is satisfied, the absence of an unfavorable tumor grade, vascular invasion, tumor budding, and extensive submucosal invasion would be the strict criteria for a wait-and-see policy.
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Adenocarcinoma/epidemiología , Adenocarcinoma/secundario , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/patología , Adenocarcinoma/cirugía , Adenocarcinoma Mucinoso/epidemiología , Adenocarcinoma Mucinoso/secundario , Adenocarcinoma Mucinoso/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Colorrectales/cirugía , Endoscopía Gastrointestinal , Femenino , Estudios de Seguimiento , Humanos , Laparotomía , Metástasis Linfática , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Factores de RiesgoRESUMEN
Compound YM-60828 was previously characterized in our laboratory as a potent, selective and orally-bioavailable Factor Xa (FXa) inhibitor. The L-shape conformation of this compound in the active site of FXa was recognized as an important factor in displaying its FXa inhibitory activity. This led to the exploration of conformationally restricted cyclic scaffolds bearing a similar active conformation. The current study investigated a novel series of benzothiadiazine-4-one based compounds as FXa inhibitors. Structure-activity relationship (SAR) investigations revealed some potent FXa inhibitors that were selected for further in vitro and ex vivo anticoagulant studies. Among them, compound 6j (YM-169920) was proved to be most effective anticoagulant in this series. The synthesis and SAR in addition to docking studies of this class of inhibitors are described.
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Benzotiadiazinas/química , Benzotiadiazinas/farmacología , Inhibidores del Factor Xa , Naftalenos/química , Naftalenos/farmacología , Piperidinas/química , Piperidinas/farmacología , Administración Oral , Animales , Anticoagulantes/síntesis química , Anticoagulantes/química , Anticoagulantes/farmacología , Benzotiadiazinas/síntesis química , Disponibilidad Biológica , Femenino , Humanos , Concentración 50 Inhibidora , Masculino , Ratones , Ratones Endogámicos ICR , Modelos Moleculares , Conformación Molecular , Naftalenos/síntesis química , Piperidinas/síntesis química , Tiempo de Protrombina , Saimiri , Relación Estructura-Actividad , Trombina/antagonistas & inhibidores , Inhibidores de Tripsina/síntesis química , Inhibidores de Tripsina/química , Inhibidores de Tripsina/farmacologíaRESUMEN
The stress-responsive genes expressed against the exogenous addition of dibenzo-p-dioxin from the lignin-degrading basidiomycete, Phanerochaete chrysosporium, were determined utilizing a differential display reverse transcription-PCR technique. Six cDNA fragments, exhibiting a high homology with various proteins from other microorganisms, were identified via a BLAST search; that is, NADH-ubiquinone oxidoreductase (NUO), ATP/ADP carrier, uric acid-xanthine permease, manganese superoxide dismutase, 3-hydroxybutyryl-coenzyme A dehydrogenase, and cytoskeletal protein. The expression of NUO was also up-regulated by catechol and trihydroxybenzene but not by dibenzofuran, suggesting that NUO expression was initiated by the formation of quinone products through the reaction of extracellular one-electron oxidizing enzymes with dibenzo-p-dioxin.
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Dioxinas/toxicidad , Lignina/metabolismo , Phanerochaete/efectos de los fármacos , Phanerochaete/genética , Perfilación de la Expresión Génica , Regulación Fúngica de la Expresión Génica/efectos de los fármacos , Homeostasis/fisiología , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/genética , Phanerochaete/metabolismoRESUMEN
Factor Xa (FXa) is a serine protease which plays a pivotal role in the coagulation cascade. The inhibition of FXa has received great interest as a potential target for the development of new antithrombotic drug. Herein we describe a series of novel 7-amidino-2-naphthoanilide and 7-amidino-2-naphthalensulfonanilide derivatives which are potent FXa inhibitors. These scaffolds are rigid and are allowed to adopt an L-shape conformation which was estimated as the active conformation based on a docking study of YM-60828 with FXa. Optimization of the side chain at the central aniline nitrogen of 7-amidino-2-naphthoanilide has led to several potent and orally active FXa inhibitors. 5h (YM-169964), the best compound of these series, showed potent FXa inhibitory activity (IC(50)=3.9nM) and effectively prolonged prothrombin time by 9.6-fold ex vivo at an oral dose of 3mg/kg in squirrel monkeys.
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Anilidas/síntesis química , Anticoagulantes/síntesis química , Inhibidores del Factor Xa , Administración Oral , Anilidas/farmacocinética , Anilidas/farmacología , Animales , Anticoagulantes/farmacocinética , Anticoagulantes/farmacología , Disponibilidad Biológica , Diseño de Fármacos , Femenino , Masculino , Ratones , Naftalenos/síntesis química , Naftalenos/farmacocinética , Naftalenos/farmacología , Piperidinas/síntesis química , Piperidinas/farmacocinética , Piperidinas/farmacología , Tiempo de Protrombina , Saimiri , Inhibidores de Serina Proteinasa/síntesis química , Inhibidores de Serina Proteinasa/farmacocinética , Inhibidores de Serina Proteinasa/farmacología , Relación Estructura-ActividadRESUMEN
Since Factor Xa (FXa) is well known to play a central role in thrombosis and hemostasis, inhibition of FXa is an attractive target for antithrombotic strategies. As a part of our investigation of a non-peptide, orally available FXa inhibitor, we found that a series of N-[(7-amidino-2-naphthyl)methyl]aniline derivatives possessed potent and selective inhibitory activities. Structure--activity relationship (SAR) of the substituent (R(1)) on the central aniline moiety suggested that increasing lipophilicity caused a detrimental effect on anticoagulant activity (prothrombin time assay) in plasma. Several compounds bearing a hydrophilic substituent in R(1) showed not only potent FXa inhibitory activities but also high anticoagulant activities. The best compound in this series was sulfamoylacetic acid derivative (YM-60828) which was a potent, selective and orally bioavailable FXa inhibitor and was chosen for clinical development.