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11.
Li Q Wang GT Li T Gwaltney SL Woods KW Claiborne A Wang X Gu W Cohen J Stoll VS Hutchins C Frost D Rosenberg SH Sham HL 《Bioorganic & medicinal chemistry letters》2004,14(21):5371-5376
A series of imidazole-containing methyl ethers (4-5) have been designed and synthesized as potent and selective farnesyltransferase inhibitors (FTIs) by transposition of the D-ring to the methyl group on the imidazole of the previously reported FTIs 3. Several compounds such as 4h and 5b demonstrate superior enzymatic activity to the current benchmark compound tipifarnib (1) with IC(50) values in the lower subnanomolar range, while maintaining excellent cellular activity comparable to tipifarnib. The compounds are characterized as being simple, easier to make, and possess no chiral center involved. 相似文献
12.
Li Q Claiborne A Li T Hasvold L Stoll VS Muchmore S Jakob CG Gu W Cohen J Hutchins C Frost D Rosenberg SH Sham HL 《Bioorganic & medicinal chemistry letters》2004,14(21):5367-5370
As a part of our efforts to identify potent inhibitors of farnesyltransferase (FTase), modification of the structure of tipifarnib through structure-based design was undertaken by replacing the 2-quinolones with 4-quinolones and pyridones, and subsequent relocation of the D-ring to the N-methyl group on the imidazole ring. This study has yielded a novel series of potent and selective FTase inhibitors. The X-ray structure of tipifarnib (1) in complex with FTase was described. 相似文献
13.
Gwaltney SL O'Connor SJ Nelson LT Sullivan GM Imade H Wang W Hasvold L Li Q Cohen J Gu WZ Tahir SK Bauch J Marsh K Ng SC Frost DJ Zhang H Muchmore S Jakob CG Stoll V Hutchins C Rosenberg SH Sham HL 《Bioorganic & medicinal chemistry letters》2003,13(7):1363-1366
Inhibitors of farnesyltransferase are effective against a variety of tumors in mouse models of cancer. Clinical trials to evaluate these agents in humans are ongoing. In our effort to develop new farnesyltransferase inhibitors, we have discovered bioavailable aryl tetrahydropyridines that are potent in cell culture. The design, synthesis, SAR and biological properties of these compounds will be discussed. 相似文献
14.
The Rho GTPases Rac1 and Cdc42 have been implicated in the regulation of axon outgrowth and guidance. However, the downstream effector pathways through which these GTPases exert their effects on axon development are not well characterized. Here, we report that axon outgrowth defects within specific subsets of motoneurons expressing constitutively active Drosophila Rac1 largely persist even with the addition of an effector-loop mutation to Rac1 that disrupts its ability to bind to p21-activated kinase (Pak) and other Cdc42/Rac1 interactive-binding (CRIB)-motif effector proteins. While hyperactivation of Pak itself does not lead to axon outgrowth defects as when Rac1 is constitutively activated, live analysis reveals that it can alter filopodial activity within specific subsets of neurons similar to constitutive activation of Cdc42. Moreover, we show that the axon guidance defects induced by constitutive activation of Cdc42 persist even in the absence of Pak activity. Our results suggest that (1) Rac1 controls axon outgrowth through downstream effector pathways distinct from Pak, (2) Cdc42 controls axon guidance through both Pak and other CRIB effectors, and (3) Pak's primary contribution to in vivo axon development is to regulate filopodial dynamics that influence growth cone guidance. 相似文献
15.
Sham HL Zhao C Li L Betebenner DA Saldivar A Vasavanonda S Kempf DJ Plattner JJ Norbeck DW 《Bioorganic & medicinal chemistry letters》2002,12(21):3101-3103
The HIV protease inhibitor Lopinavir has a pseudosymmetric core unit incorporating benzyl groups at both P-1, P-1' positions. A series of analogues incorporating non-aromatic side chains at the P-1 position were synthesized and the structure-activity relationships explored. 相似文献
16.
17.
Three cdg Operons Control Cellular Turnover of Cyclic Di-GMP in Acetobacter xylinum: Genetic Organization and Occurrence of Conserved Domains in Isoenzymes 总被引:5,自引:0,他引:5 下载免费PDF全文
18.
Yangbo Sun Chao Qiang Jiang Kar Keung Cheng Wei Sen Zhang Gabriel M. Leung Tai Hing Lam C. Mary Schooling 《PloS one》2015,10(8)
Objective
To examine the adjusted associations of fruit consumption and vegetable consumption with the Framingham score and its components in the non-Western setting of Southern China, considering health status.Method
Linear regression was used to assess the cross-sectional associations of fruit and vegetable consumption with the Framingham score and its components, among 19,518 older Chinese (≥50 years) from the Guangzhou Biobank Cohort Study in Southern China (2003–2006), and whether these differed by health status.Results
The association of fruit consumption with the Framingham score varied by health status (P-value<0.001), but not vegetable consumption (P-value 0.51). Fruit consumption was associated with a lower Framingham score (-0.04 per portions/day, 95% confidence interval (CI) -0.08 to -0.004) among participants in poor health, adjusted for age, sex, recruitment phase, socio-economic position and lifestyle. However, similarly adjusted, fruit consumption was associated with a higher Framingham score (0.05, 95% CI 0.02 to 0.09) among participants in good health, perhaps due to a positive association of fruit consumption with fasting glucose. Similarly adjusted, vegetable consumption was associated with a higher Framingham score (0.03, 95% CI 0.01 to 0.05) among all participants, with no difference by health status.Conclusion
This large study from a non-western setting found that fruit and vegetable consumption was barely associated with the Framingham score, or major CVD risk factors. 相似文献19.
Tong Y Claiborne A Pyzytulinska M Tao ZF Stewart KD Kovar P Chen Z Credo RB Guan R Merta PJ Zhang H Bouska J Everitt EA Murry BP Hickman D Stratton TJ Wu J Rosenberg SH Sham HL Sowin TJ Lin NH 《Bioorganic & medicinal chemistry letters》2007,17(13):3618-3623
A study on substitutions at the four open positions on the phenyl ring of the 1,4-dihydroindeno[1,2-c]pyrazoles as potent CHK-1 inhibitors is described. Bis-substitution at both the 6- and 7-positions led to inhibitors with IC(50) values below 0.3nM. The compound with the best overall activities (36) was able to potentiate the anti-proliferative effect of doxorubicin in HeLa cells by at least 47-fold. Physicochemical, metabolic, and pharmacokinetic properties of selected inhibitors are also disclosed. 相似文献
20.
Fui Chin Chong Beng Ti Tey Zanariah Mohd Dom Kok Hing Cheong Budiatman Satiawihardja Mohd Nordin Ibrahim Russly Abdul Rahman Dayang Radiah Awang Biak Tau Chuan Ling 《Biotechnology and Bioprocess Engineering》2007,12(3):250-256
Rice bran lipase (RBL) was delipidated to enhance its stability in organic solvent and its esterification activity at elevated
temperature. The esterification activity of delipidated RBL increased as temperature was increased from 45 to 65°C. The esterification
activity of delipidated RBL at 65°C was about 14 times greater than that of the non-delipidated RBL. As temperature was further
increased to 75°C, the non-delipidated RBL lost all esterification activity, whereas the delipidated RBL retained approximately
48% of its esterilication activity. The delipidated RBL maintained a relative esterification activity greater than 80% after
16 h of incubation in hexane, whereas the non-delipidated RBL maintained a relative esterification activity of only 50%. A
method for production of acylglycerol using delipidated RBL to esterify palm oil fatty acid distillate (PFAD) with glycerol
in hexane was successfully developed. The effects of reaction temperatures and type of water removal agents (silica gel and
molecular sieve) on the degree of esterification were also examined. A 4 h reaction at 65°C, catalyzed by delipidated RBL
and using silica gel as the water removal agent resulted in 53.8% esterification. Thin layer chromatography analysis suggested
that the esterified product was primarily comprised of mono-and di-acylglycerols. 相似文献