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1.
J Org Chem ; 87(12): 7665-7672, 2022 Jun 17.
Artículo en Inglés | MEDLINE | ID: mdl-35647791

RESUMEN

To explore the reaction universality of bridge nitration, the mononitration of different p-tert-butylcalix[4]arene derivatives was executed with tert-butyl nitrite as a nitration reagent. The effects of calix[4]arene conformations, substituents on the lower rim, and reaction conditions on bridge mononitration are systematically studied. The bridge nitration of p-tert-butylcalix[4]arene derivatives in 1,3-alternate, 1,2-alternate, and partial cone conformations can be smoothly executed while that of p-tert-butylcalix[4]arene derivatives strictly regulated in a cone conformation cannot. The nitration product complexity shows a positive correlation with the bridge-hydrogen types, and the optimal bridge-mononitrated substrate is calix[4]arene with only one bridge-hydrogen type. The electron-withdrawing substituent on the lower rim is apparently beneficial for the bridge mononitration. As a result, a variety of bridging chiral p-tert-butylcalix[4]arenes with a mononitro bridge substituent have been successfully synthesized. The highest bridge-mononitrated yield can reach 27% from 1,3-alternate p-tert-butylcalix[4]arene biscrown-5 under optimal reaction conditions.

2.
J Org Chem ; 86(5): 3952-3959, 2021 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-33577735

RESUMEN

In order to prepare bridging chiral p-tert-butylcalix[4]crown-5 with a mononitro bridge substituent in a 1,3-alternate conformation, a mononitration method of calix[4]arene bridging methylene has been first developed with tert-butyl nitrite as a nitration reagent. The effects of solvent, reaction temperature, reaction time, and nitration reagent dosage on bridge mononitration have been deeply explored to obtain an optimal nitration condition. The facile nitration presents a new key for calix[4]arene bridge derivatization. After further modification and diastereoisomeric resolution, a pair of bridging chiral p-tert-butylcalix[4]arenes with a monoamino bridge substituent were produced from the bridge-mono-nitrated calix[4]arene. Their preliminary catalysis results in the Henry reaction show good catalytic activities (up to 95% yield) and still low but obviously enhanced enantioselectivities (up to 22.3% ee from 7a, 6% ee from 1), which confirms that the structural transformation indeed improves asymmetric catalysis performances of bridging chiral calix[4]crown-5 amines in a 1,3-alternate conformation.

3.
Med Sci Monit ; 27: e929152, 2021 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-33737504

RESUMEN

BACKGROUND Lacrimal gland pleomorphic adenoma (LGPA) is the most common clinically benign epithelial tumor of the lacrimal gland and is predominantly comprised of epithelial cells and interstitial components. At present, the exact pathogenesis of LGPA remains unclear. Previous research has indicated that the occurrence of LGPA may be related to excessive cell proliferation. MATERIAL AND METHODS This study observed the clinicopathological characteristics of LGPA and investigated the tumorigenesis mechanism of cell over-proliferation caused by the imbalance between apoptosis and proliferation. A total of 27 cases were collected from the Department of Ophthalmology of the Affiliated Hospital of Chengde Medical University and the Third Medical Center of Chinese PLA General Hospital from April 2017 to November 2019. Hematoxylin-eosin (HE) staining and immunohistochemical staining were used to observe the pathological characteristics and analyze the expression of bcl-2 and bax in the lacrimal gland. RESULTS Compared with normal lacrimal gland tissues, LGPA tumor tissues had obvious changes in pathological morphology. The expression of bcl-2 in LGPA lesion tissues was dramatically higher (P<0.001), the expression of bax was not significantly different between groups (P=0.25), but the ratio of bcl-2/bax was significantly higher in tumor tissues (P=0.01). CONCLUSIONS We found that the lacrimal gland tumor tissues had obvious excessive proliferation in pathomorphology, which revealed the necessity of complete surgical removal of the capsule from the perspective of pathological morphology and provided a theoretical basis for the hypothesis that the imbalance between apoptosis and proliferation could lead to cell hyperproliferation.


Asunto(s)
Adenoma Pleomórfico/metabolismo , Adenoma Pleomórfico/patología , Aparato Lagrimal/patología , Adulto , Apoptosis/fisiología , Carcinogénesis/metabolismo , Proliferación Celular/fisiología , Transformación Celular Neoplásica/patología , Neoplasias del Ojo/patología , Neoplasias del Ojo/cirugía , Femenino , Humanos , Enfermedades del Aparato Lagrimal/patología , Enfermedades del Aparato Lagrimal/cirugía , Masculino , Persona de Mediana Edad , Neoplasias Glandulares y Epiteliales/patología , Proteínas Proto-Oncogénicas c-bcl-2/análisis , Estudios Retrospectivos , Tomografía Computarizada por Rayos X/métodos , Proteína X Asociada a bcl-2/análisis
4.
J Enzyme Inhib Med Chem ; 35(1): 682-691, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-32148108

RESUMEN

Thirty-six novel threoninamide carbamate derivatives were designed and synthesised using active fragment-based pharmacophore model. Antifungal activities of these compounds were tested against Oomycete fungi Phytophthora capsici in vitro and in vivo. Interestingly, compound I-1, I-2, I-3, I-6 and I-7 exhibited moderate control effect (>50%) against Pseudoperonospora cubensis in greenhouse at 6.25 µg/mL, which is better than that of control. Meanwhile most of these compounds exhibited significant inhibitory against P. capsici. The other nine fungi were also tested. More importantly, some compounds exhibited remarkably high activities against Sclerotinia sclerotiorum, P. piricola and R. solan in vitro with EC50 values of 3.74-9.76 µg/mL. It is possible that the model is reliabile and this method can be used to discover lead compounds for the development of fungicides.


Asunto(s)
Amidas/farmacología , Antifúngicos/farmacología , Diseño de Fármacos , Hongos/efectos de los fármacos , Treonina/farmacología , Amidas/síntesis química , Amidas/química , Antifúngicos/síntesis química , Antifúngicos/química , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-Actividad , Treonina/síntesis química , Treonina/química
5.
Molecules ; 17(9): 10414-28, 2012 Aug 31.
Artículo en Inglés | MEDLINE | ID: mdl-22941222

RESUMEN

In our search for environmentally benign insecticides with high activity, low toxicity and low residue, a novel series of amides containing N- pyridylpyrazole moieties were designed and synthesized. The structures of the title compounds were characterized and confirmed by 1H-NMR and elemental analysis. Furthermore, the structure of compound 7l was determined by single crystal X-ray diffraction. The preliminary bioassay tests showed that some of them exhibited good insecticidal activities against Mythimna separata Walker, Plutella xylostella (Linnaeus, 1758) and Laphygma exigua Hübner.


Asunto(s)
Amidas/química , Amidas/síntesis química , Insecticidas/química , Insecticidas/síntesis química , Mariposas Nocturnas , Pirazoles/análisis , Animales , Diseño de Fármacos , Estructura Molecular , Pirazoles/química , Relación Estructura-Actividad
6.
Acta Crystallogr Sect E Struct Rep Online ; 67(Pt 12): o3433, 2011 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-22199914

RESUMEN

The title compound, C(19)H(15)ClN(2)O(5)S, contains two mol-ecules (A and B) in the asymmetric unit. In mol-ecule A, the dihedral angles between the thia-zole ring and the pendant chloro-benzene and nitro-benzene rings are 72.14 (15) and 3.03 (15)°, respectively. The corresponding angles for mol-ecule B are 45.56 (16) and 1.51 (14)°, respectively. In the crystal, both mol-ecules form inversion dimers linked by pairs of weak C-H⋯O inter-actions.

7.
Biochem Biophys Res Commun ; 401(2): 188-91, 2010 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-20849817

RESUMEN

Owing to its unique function in assisting the release of newly formed virus particles from the surface of an infected cell, neuraminidase, an antigenic glycoprotein enzyme, is a main target for drug design against influenza viruses. The group-1 neuraminidase of influenza virus possesses a 150-cavity, which is adjacent to the active pocket, and which renders conformational change from the 'open' form to the 'closed' form when the enzyme is binding with a ligand. Using AutoGrow evolutionary algorithm, one very unique fragment is screened out from the fragment databases by exploiting additional interactions with the 150-cavity. Subsequently, three derivatives were constructed by linking the unique fragment to oseltamivir at its three different sites. The three derivatives thus formed show much stronger inhibition power than oseltamivir, and hence may become excellent candidates for developing new and more powerful drugs for treating influenza. Or at the very least, the findings may stimulate new strategy or provide useful insights for working on the target vitally important to the health of human beings.


Asunto(s)
Antivirales/farmacología , Inhibidores Enzimáticos/farmacología , Proteína HN/efectos de los fármacos , Orthomyxoviridae/enzimología , Oseltamivir/análogos & derivados , Proteína HN/química , Humanos , Orthomyxoviridae/efectos de los fármacos , Conformación Proteica
8.
Acta Crystallogr Sect E Struct Rep Online ; 66(Pt 6): o1308, 2010 May 12.
Artículo en Inglés | MEDLINE | ID: mdl-21579403

RESUMEN

In the title compound, C(10)H(10)N(2)O(3), the dihedral angle between the benzene and imidazolidine rings is 6.0 (4)°, consistent with an essentially planar mol-ecule. In the crystal, inter-molecular N-H⋯O hydrogen bonding between centrosymmetrically related mol-ecules leads to loosely associated dimeric aggregates. These are connected into a three-dimensional network by C-H⋯O inter-actions, as well as π-π inter-actions [centroid-centroid distances = 3.705 (3) and 3.622 (3) Å] between the imidazolidine and benzene rings.

9.
Acta Crystallogr Sect E Struct Rep Online ; 66(Pt 8): o2027, 2010 Jul 14.
Artículo en Inglés | MEDLINE | ID: mdl-21588337

RESUMEN

In the title mol-ecule, C(11)H(12)N(2)O(4), the dihedral angle between the benzene ring and imidazolidine ring is 7.1 (5)°. In the crystal structure, the hy-droxy groups are involved in the formation of inter-molecular O-H⋯O hydrogen bonds, which link the mol-ecules related by translation into C(2) chains along the b axis.

10.
Acta Crystallogr Sect E Struct Rep Online ; 66(Pt 11): o2961, 2010 Oct 30.
Artículo en Inglés | MEDLINE | ID: mdl-21589129

RESUMEN

In the title compound, C(17)H(14)BrClN(4)O(2), the pyrazole ring is almost coplanar with the benzene ring [dihedral angle = 0.5 (2)°], whereas the pyrazole ring is close to perpendicular to the 3-chloro-pyridine ring [dihedral angle = 73.7 (2)°]. An intra-molecular C-H⋯O hydrogen bond occurs. The dominant inter-action in the crystal packing is an N-H⋯N hydrogen bond, which generates a chain along the c axis. Weak inter-molecular C-H⋯O and C-H⋯N contacts are also observed.

11.
Int J Ophthalmol ; 13(6): 902-906, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32566500

RESUMEN

AIM: To study the imaging characteristics of lacrimal punctum lesion with optical coherence tomography (OCT), and provide imaging basis for the diagnosis and treatment of lacrimal punctum diseases. METHODS: A total of 25 patients (28 eyes) with epiphora and lacrimal puncta lesions were enrolled. Lacrimal puncta lesions included: punctum membrane obstruction in 7 cases (9 eyes), punctum agenesis in 1 case (1 eye), a mass protruded from the punctum in 1 case (1 eye), slit puncta in 1 case (1 eye), peri-puncta mass in 2 cases (2 eyes), chronic dacryocystitis in 4 cases (4 eyes), and primary puncta stenosis in 9 cases (10 eyes; 3 eyes mild, 4 eyes moderate and 3 eyes severe). All patients were examined by slit lamp microscopy and OCT to observe the morphological characteristics of abnormal punctum. RESULTS: Two types of complete membrane obstruction and incomplete membrane obstruction of puncta were observed in OCT images of 7 patients. No lacrimal punctum and lacrimal canalicular cavity were found in 1 case with punctum agenesis. OCT images showed that a narrow lumen remained in the lacrimal puncta in 1 patient with a mass protruded from the punctum. OCT of punctum in a patient with slit punctum after stent placement showed stent and abnormal lacrimal structure. No abnormal intraluminal structure was found in 2 cases of peri-puncta mass after OCT scan, and the lacunar space was narrower than that of the contralateral eye. OCT of puncta in 4 patients with chronic dacryocystitis showed that pus floated in tear with lump-like medium-low reflex. In 9 patients with primary lacrimal puncta stenosis, OCT image could clearly show the changes of puncta lumen in different degrees and shapes. CONCLUSION: OCT is feasible for the examination of pathological punctum, and can provide imaging basis for the diagnosis and treatment of punctum disease.

12.
J Biomol Struct Dyn ; 38(13): 3814-3824, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31490104

RESUMEN

Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of insulin signaling pathway, and more and more studies have shown that it is a potential target for the treatment of type 2 diabetes mellitus (T2DM). In this study, 17 new 4-thiazolinone derivatives were designed and synthesized as novel PTP1B inhibitors, and ADMET prediction confirmed that these compounds were to be drug-like. In vitro enzyme activity experiments were performed on these compounds, and it was found that a plurality of compounds had good inhibitory activity and high selectivity against PTP1B protein. Among them, compound 7p exhibited the best inhibitory activity with an IC50 of 0.92 µM. The binding mode of compound 7p and PTP1B protein was explored, revealing the reason for its high efficiency. In addition, molecular dynamics simulations for the PTP1BWT and PTP1Bcomp#7p systems revealed the effects of compound 7p on PTP1B protein at the molecular level. In summary, the study reported for the first time that 4-thiazolinone derivatives as a novel PTP1B inhibitor had good inhibitory activity and selectivity for the treatment of T2DM, providing more options for the development of PTP1B inhibitors. AbbreviationsBBBblood-brain barrierCDC25Bcell division cycle 25 homolog BCYP2D6Cytochrome P450 2D6 bindingDCCMdynamic cross-correlation mapDSDiscovery StudioH bondhydrogen bondHIAhuman intestinal absorptionLARleukocyte antigen-related phosphataseMDmolecular dynamicsMEG-2maternal-effect germ-cell defective 2MM-PBSAmolecular mechanics Poisson Boltzmann surface area)PCAprincipal component analysisPDBProtein Data BankpNPPp-nitrophenyl phosphatePPBplasma protein bindingPTP1Bprotein tyrosine phosphotase 1BRMSDroot mean square deviationRMSFroot mean square fluctuationSHP-1src homologous phosphatase-1SHP-2src homologous phosphatase-2SPCsingle-point chargeTCPTPT cell protein tyrosine phosphataseT2DMType 2 diabetes mellitusVDWvan der WaalsCommunicated by Ramaswamy H. Sarma.


Asunto(s)
Inhibidores Enzimáticos , Proteína Tirosina Fosfatasa no Receptora Tipo 1/antagonistas & inhibidores , Diabetes Mellitus Tipo 2 , Inhibidores Enzimáticos/farmacología , Humanos , Insulina , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Relación Estructura-Actividad
13.
J Enzyme Inhib Med Chem ; 24(2): 545-52, 2009 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18763167

RESUMEN

Ketol-acid reductoisomerase (KARI; EC 1.1.1.86) catalyzes the second common step in branched-chain amino acid biosynthesis. The catalyzed process consists of two steps, the first of which is an alkyl migration from one carbon atom to its neighboring atom. The likely transition state is a cyclopropane derivative, thus a new series of cyclopropanecarbonyl thiourea derivatives were designed and synthesized involving a one-pot phase transfer catalyzed reaction. Rice KARI inhibitory activity of these compounds were evaluated and the 5-butyl substituted (3e) and 3-pyridinyl substituted (3n) compounds reached 100% at 100 microg x mL(- 1). Structure-activity relationship shows that longer chain derivatives had higher KARI inhibitory activity. Meanwhile substitution of the 4-position of the benzene ring had higher KARI inhibitory activity than that of the 2 and 3-position. Auto-Dock was used to predict the binding mode of 3n. This was done by analyzing the interaction of compound 3n with the active sites of the available spinach KARI. This was in accord with the results analyzed by the frontier molecular orbital theory.


Asunto(s)
Inhibidores Enzimáticos/química , Cetoácido Reductoisomerasa/antagonistas & inhibidores , Tiourea/química , Sitios de Unión , Dominio Catalítico , Inhibidores Enzimáticos/farmacología , Cetoácido Reductoisomerasa/metabolismo , Relación Estructura-Actividad , Especificidad por Sustrato , Tiourea/farmacología
14.
Oncotarget ; 8(20): 33225-33240, 2017 May 16.
Artículo en Inglés | MEDLINE | ID: mdl-28402259

RESUMEN

Cell division cycle 25B is a key cell cycle regulator and widely considered as potent clinical drug target for cancers. This research focused on identifying potential compounds in theory which are able to disrupt transient interactions between CDC25B and its CDK2/Cyclin A substrate.By using the method of ZDOCK and RDOCK, the most optimized 3D structure of CDK2/Cyclin A in complex with CDC25B was constructed and validated using two methods: 1) the superimposition of proteins; 2) analysis of the hydrogen bond distances of Arg 488(N1)-Asp 206(OD1), Arg 492(NE)-Asp 206(OD1), Arg 492(N1)-Asp 206(OD2) and Tyr 497(NE)-Asp 210(OD1). A series of new compounds was gained through searching the fragment database derived from ZINC based on the known inhibitor-compound 7 by the means of "replace fragment" technique. The compounds acquired via meeting the requirements of the absorption, distribution, metabolism, and excretion (ADME) predictions. Finally, 12 compounds with better binding affinity were identified. The comp#1, as a representative, was selected to be synthesized and assayed for their CDC25B inhibitory activities. The comp#1 exhibited mild inhibitory activities against human CDC25B with IC50 values at about 39.02 µM. Molecular Dynamic (MD) simulation revealed that the new inhibitor-comp#1 had favorable conformations for binding to CDC25B and disturbing the interactions between CDC25B and CDK2/Cyclin A.


Asunto(s)
Antineoplásicos/química , Ciclina A/química , Quinasa 2 Dependiente de la Ciclina/química , Diseño de Fármacos , Inhibidores Enzimáticos/química , Modelos Moleculares , Fosfatasas cdc25/química , Antineoplásicos/farmacología , Sitios de Unión , Ciclina A/metabolismo , Quinasa 2 Dependiente de la Ciclina/metabolismo , Inhibidores Enzimáticos/farmacología , Humanos , Enlace de Hidrógeno , Conformación Molecular , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Complejos Multiproteicos/química , Complejos Multiproteicos/metabolismo , Unión Proteica/efectos de los fármacos , Relación Estructura-Actividad , Fosfatasas cdc25/antagonistas & inhibidores , Fosfatasas cdc25/metabolismo
15.
Zhonghua Yan Ke Za Zhi ; 41(6): 523-6, 2005 Jun.
Artículo en Zh | MEDLINE | ID: mdl-16008913

RESUMEN

OBJECTIVE: To investigate the mutations of the BIGH3 gene in patients with lattice corneal dystrophy in China. METHODS: Molecular genetic analysis was performed on DNA extracted from peripheral leukocytes from eight patients with lattice corneal dystrophy and without systemic amyloidosis in Tongren Ophthalmic Center. Exons 4, 12, 14 of the BIGH3 gene were amplified by polymerase chain reaction and were sequenced directly. The cornea of these patients were examined with slit lamp biomicroscope and photographed. At the same time, 32 normal subjects were recruited in the molecular genetic analysis as the controls. RESULTS: Three LCDI patients had R124C mutation (one missense mutation at position 417 C-->G of exon 4) in the BIGH3 gene, all of them were heterozygous. The other five patients showed different H626R mutations at position 1924 from A to G of the BIGH3 gene in exon 14, all of them were heterozygous too. The clinical appearance in patients with H626R mutation was an intermediate type between LCDI and LCDIII or LCDIIIA. CONCLUSIONS: R124C mutation and H626R mutation are detected in Chinese patients with lattice corneal dystrophy. It seems that H626R mutation not only presents in British and French patients, but also can be found in Asia patients.


Asunto(s)
Distrofias Hereditarias de la Córnea/genética , Proteínas de la Matriz Extracelular/genética , Mutación Missense , Factor de Crecimiento Transformador beta/genética , Adulto , Pueblo Asiatico/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Biología Molecular , Linaje
16.
Eur J Med Chem ; 103: 91-104, 2015 Oct 20.
Artículo en Inglés | MEDLINE | ID: mdl-26342135

RESUMEN

Protein tyrosine phosphatase 1B (PTP1B) plays a vital role in the regulation of insulin sensitivity and dephosphorylation of the insulin receptor, so PTP1B inhibitors may be potential agents to treat type 2 diabetes. In this work, a series of novel imidazolidine-2,4-dione derivatives were designed, synthesized and assayed for their PTP1B inhibitory activities. These compounds exhibited potent activities with IC50 values at 0.57-172 µM. A 3D-QSAR study using CoMFA and CoMSIA techniques was carried out to explore structure activity relationship of these molecules. The CoMSIA model was more predictive with q(2) = 0.777, r(2) = 0.999, SEE = 0.013 and r(2)pred = 0.836, while the CoMFA model gave q(2) = 0.543, r(2) = 0.998, SEE = 0.029 and r(2)pred = 0.754. The contour maps derived from the best CoMFA and CoMSIA models combined with docking analysis provided good insights into the structural features relevant to the bioactivity, and could be used in the molecular design of novel imidazolidine-2,4-dione derivatives.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Imidazolidinas/farmacología , Proteína Tirosina Fosfatasa no Receptora Tipo 1/antagonistas & inhibidores , Relación Estructura-Actividad Cuantitativa , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Imidazolidinas/síntesis química , Imidazolidinas/química , Modelos Moleculares , Estructura Molecular , Proteína Tirosina Fosfatasa no Receptora Tipo 1/metabolismo , Relación Estructura-Actividad
17.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 21(1): 32-4, 2004 Feb.
Artículo en Zh | MEDLINE | ID: mdl-14767905

RESUMEN

OBJECTIVE: To identify the mutations of BIGH3 gene in Chinese patients with corneal dystrophies. METHODS: Polymerase chain reaction in exon 4, exon 12 and direct DNA sequencing of BIGH3 gene were performed in fifteen patients with corneal dystrophies and ten normal individuals as controls. RESULTS: Mutations in BIGH3 gene were detected in all the patients with corneal dystrophies. BIGH3 gene mutations were not found in normal subjects. Twelve patients with Avellino corneal dystrophy had the missense mutation R124H in the BIGH3 gene. Three patients with granular corneal dystrophy had the missense mutation R555W in the BIGH3 gene. CONCLUSION: R124H and R555W mutations in BIGH3 gene were found in the patients with Avellino and granular corneal dystrophies. Avellino corneal dystrophy associated with the R124H mutation is the most common form in the corneal dystrophies resulting from BIGH3 gene mutations. Condons 124 and 555 are also the hot spots for the mutations in the BIGH3 gene in the Chinese patients with corneal dystrophies.


Asunto(s)
Distrofias Hereditarias de la Córnea/genética , Proteínas de la Matriz Extracelular/genética , Mutación Missense , Factor de Crecimiento Transformador beta/genética , Adolescente , Adulto , Anciano , Secuencia de Bases , Distrofias Hereditarias de la Córnea/patología , ADN/química , ADN/genética , Análisis Mutacional de ADN , Femenino , Humanos , Masculino , Persona de Mediana Edad
18.
Zhonghua Yan Ke Za Zhi ; 40(7): 465-70, 2004 Jul.
Artículo en Zh | MEDLINE | ID: mdl-15454061

RESUMEN

OBJECTIVE: To analyze the image of corneas with Fuchs endothelial dystrophy using confocal microscopy in vivo. METHODS: Central corneas of 38 eyes (19 patients aged 33 approximately 76 years) were examined using scanning slit confocal microscopy in vivo after being diagnosed with Fuchs endothelial dystrophy. They were divided into two groups namely symptomatic (19 eyes) and asymptomatic (19 eyes). The control group comprised of 30 normal eyes. The images were analyzed visually for morphology of corneas and the densities of cells, as well as the diameter of the guttae and the corneal nerves were counted by NAVIS software. RESULTS: (1) In the symptomatic groups, confocal microscopy revealed guttae in 19 eyes. The diameter of the guttae ranged from 20 to 60 micro m. The density of endothelial cells was statistically significant compared with the control group (t = 18.74, P < 0.01). Descemet's membrane was thickened in 9 eyes. Dark bands 6.0 approximately 10.8 micro m in diameter were detected in 14 eyes. All eyes showed a diffuse increased light reflection in the stroma.17 eyes exhibited an abnormal Bowman's layer: multiple focal bright reflection. 10 eyes revealed normal corneal nerves. The differences between posterior and anterior keratocyte densities in the control and study groups were not statistically significantly different (t = 0.854, 1.173; P = 0.38, 0.24 respectively). (2) In the asymptomatic groups, less number of guttae could be seen in the endothelial layer. The diameter of the guttae was 15 approximately 40 micro m. The densities of endothelial cells were not significantly different compared with control group (t = 1.998, P = 0.053). Other layers of the cornea exhibited no other abnormal phenomenon. The densities of endothelial cells between symptomatic and asymptomatic groups were statistically significantly different (t = 8.352, P < 0.01). CONCLUSIONS: Morphologic characteristics of cornea are observed by confocal microscopy in Chinese patients with Fuchs endothelial dystrophy. Preliminary results demonstrate that there is no significant difference between Chinese and western patients. Confocal microscopy allows to diagnose Fuchs dystrophy and visualize endothelial cells within the swollen cornea. And it is especially useful for patients whose endothelial cells can not be seen with non-contact specular microscopy.


Asunto(s)
Endotelio Corneal/ultraestructura , Distrofia Endotelial de Fuchs/patología , Adulto , Anciano , Córnea/ultraestructura , Femenino , Humanos , Masculino , Microscopía Confocal , Persona de Mediana Edad
19.
Comb Chem High Throughput Screen ; 17(10): 837-47, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25360618

RESUMEN

The cell division cycle 25 (Cdc25) family of proteins is a group of highly conserved dual specificity phosphatases that regulate cyclin-dependent kinases and represent a group of attractive drug targets for anticancer therapies. To develop novel Cdc25B inhibitors, the ZINC database was screened for finding optimal fragments with de novo design approaches. As a result, top 11 compounds with higher binding affinities in flexible docking were obtained, which were derived from five novel scaffolds (scaffold C) consisting of the linker-part and two isolated scaffolds (scaffold A and B)located in the two binding domains (catalytic pocket and swimming pool), respectively. The subsequent molecular docking and molecular dynamics studies showed that these compounds not only adopt more favorable conformations but also have stronger binding interaction with receptor than the inhibitors identified previously. The additional absorption, distribution, metabolism, excretion and toxicity (ADMET) predictions also indicted that the 11 compounds (especially Comp#1) hold a high potential to be novel lead compounds for anticarcinogen. Consequently, the findings reported here may at least provide a new strategy or useful insights for designing effective Cdc25B inhibitors.


Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Dominio Catalítico/efectos de los fármacos , Diseño de Fármacos , Neoplasias/tratamiento farmacológico , Fosfatasas cdc25/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Neoplasias/metabolismo , Fosfatasas cdc25/química , Fosfatasas cdc25/metabolismo
20.
Protein Pept Lett ; 21(6): 556-63, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24364859

RESUMEN

Due to the vital role in many cell regulatory processes, such as cell cycle control, survival and apoptosis, as well as growth and neurotransmitter signaling, Src homology 2 (SH2) domain-containing phosphatase 2(Shp2) has attracted considerable attention for developing drugs to treat cancers. In this study, by means of the powerful "core hopping" technique, a novel class of inhibitors was discovered based on the compound II-B08. It was observed by molecular dynamics simulations that these novel inhibitors not only possessed the same function as II-B08 did in inhibiting Shp2, but also had stronger binding to the receptor. It was further validated by the outcomes of their ADME (absorption, distribution, metabolism, and excretion) predictions that the new inhibitors hold high potential to become promising drug candidates for developing novel and powerful drugs for anticancer. Subsequently, in vitro evaluation of promising hits revealed a novel and selective inhibitor of Shp2.


Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Diseño de Fármacos , Proteína Tirosina Fosfatasa no Receptora Tipo 11/antagonistas & inhibidores , Humanos , Simulación de Dinámica Molecular , Neoplasias/tratamiento farmacológico , Proteína Tirosina Fosfatasa no Receptora Tipo 11/química , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo
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