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51.
Sorafenib is a relatively new cytostatic drug approved for the treatment of renal cell and hepatocellular carcinoma. In this report we describe the synthesis of sorafenib derivatives 4a-e which differ from sorafenib in their amide part. A 4-step synthetic pathway includes preparation of 4-chloropyridine-2-carbonyl chloride hydrochloride (1), 4-chloro-pyridine-2-carboxamides 2a-e, 4-(4-aminophenoxy)-pyridine-2-carboxamides 3a-e and the target compounds 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]-phenoxy]-pyridine-2-carboxamides 4a-e. All compounds were fully chemically characterized and evaluated for their cytostatic activity against a panel of carcinoma, lymphoma and leukemia tumour cell lines. In addition, their antimetabolic potential was investigated as well. The most prominent antiproliferative activity was obtained for compounds 4a-e (IC(50) = 1-4.3 μmol·L-1). Their potency was comparable to the potency of sorafenib, or even better. The compounds inhibited DNA, RNA and protein synthesis to a similar extent and did not discriminate between tumour cell lines and primary fibroblasts in terms of their anti-proliferative activity.  相似文献   
52.
Recently, it has been shown that the red fluorescent protein DsRed undergoes photoconversion on intense irradiation, but the mechanism of the conversion has not yet been elucidated. Upon irradiation with a nanosecond-pulsed laser at 532 nm, the chromophore of DsRed absorbing at 559 nm and emitting at 583 nm (R form) converts into a super red (SR) form absorbing at 574 nm and emitting at 595 nm. This conversion leads to a significant change in the fluorescence quantum yield from 0.7 to 0.01. Here we demonstrate that the photoconversion is the result of structural changes of the chromophore and one amino acid. Absorption, fluorescence, and vibrational spectroscopy as well as mass spectrometry suggest that a cis-to-trans isomerization of the chromophore and decarboxylation of a glutamate (E215) take place upon irradiation to form SR. At the same time, another photoproduct (B) with an absorption maximum at 386 nm appears upon irradiation. This species is assigned as a protonated form of the DsRed chromophore. It might be a mixture of several protonated DsRed forms as there is at least two ways of formation. Furthermore, the photoconversion of DsRed is proven to occur through a consecutive two-photon absorption process. Our results demonstrate the importance of the chromophore conformation in the ground state on the brightness of the protein as well as the importance of the photon flux to control/avoid the photoconversion process.  相似文献   
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The course of the reactions involved in the process of degradation of strychnine ( 1 ) to Wieland-Gumlich aldehyde (WGA) ( 2 ), first performed by Wieland, Kaziro & Gumlich , has been elucidated. 23-Isonitrosostrychnine hydrochloride ( 9a ) upon treatment with thionyl chloride undergoes a fragmentation (2nd order Beckmann rearrangement), thus furnishing N(a)-cyanoformyl-WGA hydrochloride ( 14a ). On heating in an acidic medium, the latter compound is transformed — at least partially via the cyclic urethane 15 — into WGA ( 2 ), which is an important keyintermediate in the syntheses of strychnine and curare alkaloids. The compound 2 can now be obtained in high purity and good yield. A corresponding degradation has been realized with quaternary analogues ( 27 → 3 ) as well as with 10-chlorostrychnine ( 58 → 62 ). 10-Chlorostrychnine ( 58 ) was prepared by chlorination of strychnine with chlorine in conc. hydrochloric acid according to Leuchs & Steinborn. As by-products of the reaction, 10, 15-dichlorostrychnine ( 59 ) and 10, 15, 19-trichlorostrychnine ( 60 ) could be identified. Starting from WGA a series of derivatives have been prepared. Special mention is made of the two epimeric methyl ethers 18 and 19 . The absolute configuration at the centre 17 of WGA and of these two substances has been established by optical comparisons of 3 epimeric pairs. The methyl ether 18 , by-product « B », is obtained if methanol is used in working up the Beckmann rearrangement products of 23-isonitrosostrychnine hydrochloride ( 9a ). A second by-product, « A », results by working up under alkaline conditions. This compound has the structure 44 with inverted configuration at centre 16. Degradation of 44 under controlled conditions leads either to WG-diol ( 42 ) or to 16-epi-WG-diol ( 51 ). Besides « A z.rdang; and « B » a series of by-products and intermediates ( 16, 17, 11a, 22. 23, 24 and 25 ) could be detected in the course of the process of strychnine degradation.  相似文献   
55.
The first example of a phosphodiester bond cleavage promoted by a highly negatively charged polyoxometalate cluster has been discovered: the hydrolysis of the phosphodiester bond in a DNA model substrate bis(p-nitrophenyl)phosphate (BNPP) is promoted by the heptamolybdate anion [Mo7O24](6-) with rates which represent an acceleration of nearly four orders of magnitude compared to the uncatalyzed cleavage.  相似文献   
56.
A methodology is proposed for the efficient determination of gradient information, when performing gradient based optimisation of an off-road vehicle’s suspension system. The methodology is applied to a computationally expensive, non-linear vehicle model, that exhibits severe numerical noise. A recreational off-road vehicle is modelled in MSC.ADAMS, and coupled to MATLAB for the execution of the optimisation. The successive approximation method, Dynamic-Q, is used for the optimisation of the spring and damper characteristics. Optimisation is performed for both ride comfort and handling. The determination of the objective function value is performed using computationally expensive numerical simulations.This paper proposes a non-linear pitch-plane model, to be used for the gradient information, when optimising ride comfort. When optimising for handling, a non-linear four wheel model, that includes roll, is used. The gradients of the objective function and constraint functions are obtained through the use of central finite differences, within Dynamic-Q, via numerical simulation using the proposed simplified models. The importance of correctly scaling these simplified models is emphasised. The models are validated against experimental results. The simplified vehicle models exhibit significantly less numerical noise than the full vehicle simulation model, and solve in significantly less computational time.  相似文献   
57.
We report the onset of wave chaos in a real-world vertical-cavity surface-emitting laser. In a joint experimental and modeling approach we demonstrate that a small deformation in one layer of the complicated laser structure changes the emission properties qualitatively. Based on the analysis of the spatial emission profiles and spectral eigenvalue spacing distributions, we attribute these changes to the transition from regular behavior to wave chaos, and justify the full analogy to two-dimensional billiards by model calculations. Hence, these lasers represent fascinating devices for wave chaos studies.  相似文献   
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