全文获取类型
收费全文 | 144篇 |
免费 | 8篇 |
出版年
2022年 | 2篇 |
2021年 | 3篇 |
2020年 | 4篇 |
2019年 | 6篇 |
2018年 | 1篇 |
2017年 | 4篇 |
2016年 | 3篇 |
2015年 | 8篇 |
2014年 | 6篇 |
2013年 | 14篇 |
2012年 | 13篇 |
2011年 | 8篇 |
2010年 | 7篇 |
2009年 | 3篇 |
2008年 | 7篇 |
2007年 | 6篇 |
2006年 | 7篇 |
2005年 | 2篇 |
2004年 | 5篇 |
2003年 | 2篇 |
2002年 | 2篇 |
2001年 | 3篇 |
2000年 | 2篇 |
1999年 | 2篇 |
1998年 | 2篇 |
1997年 | 2篇 |
1996年 | 1篇 |
1994年 | 3篇 |
1993年 | 1篇 |
1992年 | 3篇 |
1991年 | 5篇 |
1990年 | 2篇 |
1988年 | 4篇 |
1982年 | 1篇 |
1981年 | 1篇 |
1980年 | 1篇 |
1979年 | 1篇 |
1977年 | 2篇 |
1975年 | 1篇 |
1972年 | 2篇 |
排序方式: 共有152条查询结果,搜索用时 15 毫秒
61.
Motiwala H Kandre S Birar V Kadam KS Rodge A Jadhav RD Mahesh Kumar Reddy M Brahma MK Deshmukh NJ Dixit A Doshi L Gupte A Gangopadhyay AK Vishwakarma RA Srinivasan S Sharma M Nemmani KV Sharma R 《Bioorganic & medicinal chemistry letters》2011,21(19):5812-5817
The diacylglycerol acyltransferase enzyme, DGAT1, presents itself as a potential target for obesity as this enzyme is dedicated to the final committed step in triglyceride biosynthesis. Biphenyl ureas, exemplified by compound 4, have been reported to be potent hDGAT1 inhibitors. We have synthesized and evaluated 2-pyridyl and 3-pyridyl containing biaryl ureas as hDGAT1 inhibitors. Our aim was to incorporate a heteroaryl scaffold within these molecules thereby improving the cLogP profile and making these compounds more drug-like. Compounds within this series exhibited potent hDGAT1 inhibition when evaluated using an in vitro enzymatic assay. Selected compounds were also subjected to an oral fat tolerance test in mice where the percent triglyceride reduction versus a vehicle control was evaluated. Of the studied heteroaryl analogs compound 44 exhibited an in vitro IC(50) of 17nM and a plasma triglyceride reduction of 79% along with a 12-fold improvement in solubility over the biphenyl urea compound 4. 相似文献
62.
The authors report here higher throughput screening (HTS) assays for the evaluation of CYP3A4 inhibition and CYP3A4 induction in human hepatocytes using a novel CYP3A4 substrate, luciferin IPA (LIPA). Using human recombinant CYP450 isoforms, LIPA was found to be metabolized extensively by CYP3A4 but not by CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP2E1. In the 384-well plate CYP3A4 inhibition assay, the known inhibitors 1-aminobenzotriazole, erythromycin, ketoconazole, and verapamil were found to cause extensive (maximum inhibition of >80%), dose-dependent, statistically significant inhibition of LIPA metabolism. The non-CYP3A4 inhibitors diethyldithiocarbamate, quercetin, quinidine, sulfaphenazole, ticlopidine, and tranylcypromine were found to have substantially lower (maximum inhibition of <50%) or no apparent inhibitory effects in the HTS assay. In the 96-well plate induction assay, the CYP3A4 inducers rifampin, phenobarbital, carbamazepine, phenytoin, troglitazone, rosiglitazone, and pioglitazone yielded dose-dependent induction of LIPA metabolism, whereas the CYP1A2 inducers omeprazole and 3-methylcholanthrene did not display any induction in the CYP3A4 activity. The high sensitivity and specificity of the assays, the relative ease of execution, and reduced cost, time, and test material requirements suggest that the HTS assays may be applied routinely for screening a large number of chemicals in the drug discovery phase for CYP3A4 inhibitory and inducing potential. 相似文献
63.
Xanthopoulou L Ghevaria H Mantzouratou A Serhal P Doshi A Delhanty JD 《Cytogenetic and genome research》2012,136(1):21-29
Chromosome breakage is a fairly widespread phenomenon in preimplantation embryos affecting at least 10% of day 3 cleavage stage embryos. It may be detected during preimplantation genetic diagnosis (PGD). For carriers of structural chromosomal abnormalities, PGD involves the removal and testing of single blastomeres from cleavage stage embryos, aiming towards an unaffected pregnancy. Twenty-two such couples were referred for PGD, and biopsied blastomeres on day 3 and untransferred embryos (day 5/6) were tested using fluorescence in situ hybridisation (FISH) with appropriate probes. This study investigated whether chromosome breakage (a) was detected more frequently in cases where the breakpoint of the aberration was in the same chromosomal band as a fragile site and (b) was influenced by maternal age, sperm parameters, reproductive history, or the sex of the carrier parent. The frequency of breakage seemed to be independent of fragile sites, maternal age, reproductive history, and sex of the carrier parent. However, chromosome breakage was very significantly higher in embryos from male carriers with poor sperm parameters versus embryos from male carriers with normal sperm parameters. Consequently, embryos from certain couples were more prone to chromosome breakage, fragment loss, and hence chromosomally unbalanced embryos, independently of meiotic segregation. 相似文献
64.
B-Rao C Kulkarni-Almeida A Katkar KV Khanna S Ghosh U Keche A Shah P Srivastava A Korde V Nemmani KV Deshmukh NJ Dixit A Brahma MK Bahirat U Doshi L Sharma R Sivaramakrishnan H 《Bioorganic & medicinal chemistry》2012,20(9):2930-2939
In recent years, xanthine oxidase has emerged as an important target not only for gout but also for cardiovascular and metabolic disorders involving hyperuricemia. Contrary to popular belief, recent clinical trials with uricosurics have demonstrated that enhanced excretion of uric acid is, by itself, not adequate to treat hyperuricemia; simultaneous inhibition of production of uric acid by inhibition of xanthine oxidase is also important. Virtual screening of in-house synthetic library followed by in vitro and in vivo testing led to the identification of a novel scaffold for xanthine oxidase inhibition. In vitro activity results corroborated the results from molecular docking studies of the virtual screening hits. The isocytosine scaffold maintains key hydrogen bonding and pi-stacking interactions in the deep end of the xanthine-binding pocket, which anchors it in an appropriate pose to inhibit binding of xanthine and shows promise for further lead optimization using structure-based drug design approach. 相似文献
65.
66.
67.
A method is described for the simultaneous analysis of several biologically important phenylethylamines using gas chromatography/mass spectrometry. The amines are converted to N-dinitrophenyl, O-trimethylsilyl derivatives prior to their separation by gas chromatography. By using selected ion monitoring in the chemical ionization mode, we have been able to quantitate the endogenous concentrations of phenylethylamine and phenylethanolamine in rat brain. 相似文献
68.
We present an updated account of breast cancer treatment and of progress toward “precision” cancer therapy; we focus on new developments in diagnostic molecular pathology and breast cancer that have emerged during the past 2 years. Increasing awareness of new prognostic and predictive methodologies, and introduction of next generation sequencing has increased understanding of both tumor biology and clinical behavior, which offers the possibility of more appropriate therapeutic choices. It remains unclear which of these testing methodologies provides the most informative and cost-effective actionable results for predictive and prognostic pathology. It is likely, however, that an integrated “step-wise” approach that uses the traditional clinical-pathologic paradigms coordinated with molecular characterization of breast tumor tissue, will offer the most comprehensive and cost-effective options for individualized, “precision” therapy for patients with breast cancer. 相似文献
69.
André M Nicola Rosângela V Andrade Alessandra S Dantas Patrícia A Andrade Fabrício BM Arraes Larissa Fernandes Ildinete Silva-Pereira Maria Sueli S Felipe 《BMC microbiology》2008,8(1):158
Background
Paracoccidioides brasiliensis is a dimorphic fungus that causes the most prevalent systemic mycosis in Latin America. The response to heat shock is involved in pathogenesis, as this pathogen switches from mycelium to yeast forms in a temperature dependent fashion that is essential to establish infection. HSP90 is a molecular chaperone that helps in the folding and stabilization of selected polypeptides. HSP90 family members have been shown to present important roles in fungi, especially in the pathogenic species, as an immunodominant antigen and also as a potential antifungal therapeutic target. 相似文献70.
The biosorption of metal ions (Cr+3,
, Cu+2, and Ni+2) on two algal blooms (designated HD-103 and HD-104) collected locally was investigated as a function of the initial metal
ion concentration. The main constituent of HD-103 is Cladophora sp., while Spirulina sp. is present significantly in the bloom HD-104. Algal biomass HD-103 exhibited the highest Cu+2 uptake capacity (819 mg/g). This bloom adsorbed Ni+2 (504 mg/g), Cr+3 (347 mg/g), and (168 mg/g). Maximum of Ni+2 (1108 mg/g) is taken by HD-104. This species takes up 306, 202, and 576 mg/g Cr+3, , and Cu+2, respectively. Equilibrium data fit very well to both the Langmuir and the Freundlich isotherm models. The sorption process
followed the Freundlich model better. Pseudo-first-order kinetic model could describe the kinetic data. Infrared (IR) spectroscopic
data were employed to identify the site(s) of bonding. It was found that phosphate and peptide moieties participate in the
metal uptake by bloom HD-103. In the case of bloom HD-104, carboxylate and phosphate are responsible for the metal uptake.
The role of protein in metal uptake by HD-103 was investigated using polyacrylamide gel electrophoresis. 相似文献