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621.
Dr. Václav Němec Dr. Prashant Khirsariya Dr. Pavlína Janovská Paula Martín Moyano Dr. Lukáš Maier Petra Procházková Pavlína Kebková Tomáš Gybel' Dr. Benedict-Tilman Berger Dr. Apirat Chaikuad Dr. Maria Reinecke Prof. Dr. Bernhard Kuster Prof. Dr. Stefan Knapp Prof. Dr. Vítězslav Bryja Prof. Dr. Kamil Paruch 《Angewandte Chemie (International ed. in English)》2023,62(11):e202217532
Casein kinases 1 (CK1) are key signaling molecules that have emerged recently as attractive therapeutic targets in particular for the treatment of hematological malignancies. Herein, we report the identification of a new class of potent and highly selective inhibitors of CK1α, δ and ϵ. Based on their optimal in vitro and in vivo profiles and their exclusive selectivity, MU1250, MU1500 and MU1742 were selected as quality chemical probes for those CK1 isoforms. At proper concentrations, MU1250 and MU1500 allow for specific targeting of CK1δ or dual inhibition of CK1δ/ϵ in cells. The compound MU1742 also efficiently inhibits CK1α and, to our knowledge, represents the first potent and highly selective inhibitor of this enzyme. In addition, we demonstrate that the central 1H-pyrrolo[2,3-b]pyridine-imidazole pharmacophore can be used as the basis of highly selective inhibitors of other therapeutically relevant protein kinases, e.g. p38α, as exemplified by the compound MU1299. 相似文献
622.
García-Martín S Urones-Garrote E Knapp MC King G Woodward PM 《Journal of the American Chemical Society》2008,130(45):15028-15037
Transmission electron microscopy studies of the perovskite NaLaMgWO 6 reveal the formation of a complex, compositionally modulated structure. Annular dark field scanning transmission electron microscopy images and scanning transmission electron microscopy-electron energy-loss spectroscopy scans show that this modulation involves a repeating pattern of La-rich and La-poor stripes, each stripe 6 a p or approximately 24 A wide (where a p is the edge length of the simple cubic perovskite unit cell). High-resolution transmission electron microscopy images clearly show, and electron diffraction patterns confirm, a periodicity of 12 a p along either the [100] p or [010] p direction. Available evidence suggests a spontaneous separation into stripes that possess the nominal stoichiometry, NaLaMgWO 6, alternating with Na-poor/La-rich stripes that have a stoichiometry of (La x Na 1-3 x )LaMgWO 6. X-ray powder diffraction measurements are insensitive to this intricate structural complexity, which may be a more widespread feature of (A (+)Ln (3+))MM'O 6 perovskites than previously appreciated. 相似文献
623.
624.
Shan ZW Wiezorek JM Stach EA Follstaedt DM Knapp JA Mao SX 《Physical review letters》2007,98(9):095502
It is believed that the dynamics of dislocation processes during the deformation of nanocrystalline materials can only be visualized by computational simulations. Here we demonstrate that observations of dislocation processes during the deformation of nanocrystalline Ni with grain sizes as small as 10 nm can be achieved by using a combination of in situ tensile straining and high-resolution transmission electron microscopy. Trapped unit lattice dislocations are observed in strained grains as small as 5 nm, but subsequent relaxation leads to dislocation recombination. 相似文献
625.
[structure: see text]. Pactamycin, one of the most complex and densely functionalized aminocyclitol antibiotics known, presents synthetic challenges that include reactivity and sterics, relative and absolute stereochemistry, and functional group compatibility and protection. An approach is reported that features four different types of (cyclopentane) face selective functionalization reactions and results in a polyfunctionalized and appropriately protected intermediate that incorporates all the core carbons and the oxygenated functionality of the target. 相似文献
626.
Several new methods for the preparation of vinyl iodides via mercuration and thallation reactions of vinylboronic acids have been explored. Chloramine-T oxidation of alkylvinylmercury iodides or iodide treatment of alkylvinylthallium trifluoroacetate substrates, prepared from the corresponding alkylvinylboronic acid and thallic trifluoroacetate, yields the corresponding alkylvinyl iodides. These method are also efficient for the synthesis of the corresponding radioiodinated compounds. 相似文献
627.
Gesa Schfer Jelena Mili Adeeb Eldahshan Frank Gtz Kerstin Zühlke Christian Schillinger Annika Kreuchwig Jonathan M. Elkins Kamal R. AbdulAzeez Andreas Oder Marie C. Moutty Nanako Masada Monika Beerbaum Brigitte Schlegel Sylvia Niquet Peter Schmieder Gerd Krause Jens Peter vonKries Dermot M. F. Cooper Stefan Knapp Jrg Rademann Walter Rosenthal Enno Klussmann 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2013,125(46):12409-12413
628.
Molecular dynamics (MD) is a powerful in silico method to investigate the interactions between biomolecules. It solves Newton's equations of motion for atoms over a specified period of time and yields a trajectory file, containing the different spatial arrangements of atoms during the simulation. The movements and energies of each single atom are recorded. For evaluating of these simulation trajectories with regard to biomedical implications, several methods are available. Three well-known ones are the root mean square deviation (RMSD), the root mean square fluctuation (RMSF) and solvent accessible surface area (SASA). Herein, we present a novel plug-in for the software "visual molecular dynamics" (VMD) that allows an interactive 3D representation of RMSD, RMSF, and SASA, directly on the molecule. On the one hand, our plug-in is easy to handle for inexperienced users, and on the other hand, it provides a fast and flexible graphical impression of the spatial dynamics of a system for experts in the field. 相似文献
629.
Feng L Geisselbrecht Y Blanck S Wilbuer A Atilla-Gokcumen GE Filippakopoulos P Kräling K Celik MA Harms K Maksimoska J Marmorstein R Frenking G Knapp S Essen LO Meggers E 《Journal of the American Chemical Society》2011,133(15):5976-5986
The generation of synthetic compounds with exclusive target specificity is an extraordinary challenge of molecular recognition and demands novel design strategies, in particular for large and homologous protein families such as protein kinases with more than 500 members. Simple organic molecules often do not reach the necessary sophistication to fulfill this task. Here, we present six carefully tailored, stable metal-containing compounds in which unique and defined molecular geometries with natural-product-like structural complexity are constructed around octahedral ruthenium(II) or iridium(III) metal centers. Each of the six reported metal compounds displays high selectivity for an individual protein kinase, namely GSK3α, PAK1, PIM1, DAPK1, MLCK, and FLT4. Although being conventional ATP-competitive inhibitors, the combination of the unusual globular shape and rigidity characteristics, of these compounds facilitates the design of highly selective protein kinase inhibitors. Unique structural features of the octahedral coordination geometry allow novel interactions with the glycine-rich loop, which contribute significantly to binding potencies and selectivities. The sensitive correlation between metal coordination sphere and inhibition properties suggests that in this design, the metal is located at a "hot spot" within the ATP binding pocket, not too close to the hinge region where globular space is unavailable, and at the same time not too far out toward the solvent where the octahedral coordination sphere would not have a significant impact on potency and selectivity. This study thus demonstrates that inert (stable) octahedral metal complexes are sophisticated structural scaffolds for the design of highly selective chemical probes. 相似文献
630.
Gas-phase energies of 36 tautomer/isomer pairs of 18 six-membered N-heterocyclic compounds were computed quantum chemically. Among the considered B3LYP, BH&HLYP, BH&HLYP(G), and PW6B95 DFT functionals, the latter two provide accurate tautomer/isomer pair energies with root-mean-square deviations (rmsd) relative to experiments of 0.2 and 0.3 kcal/mol, respectively. Since only few (namely five) experimental data are available, 15 tautomer/isomer pair energies were computed with the very precise QCISD(T)(quadruple-ζ) method serving as reference. Relative to this reference the PW6B95 DFT functional is slightly superior to the BH&HLYP(G) functional, yielding an rmsd of 0.7 and 0.8 kcal/mol, respectively. In contrast to BH&HLYP(G), the PW6B95 DFT functional yields also accurate tautomer/isomer pair energies if zwitterionic structures are involved. The tautomer/isomer pair states possess different amounts of aromaticity. This is characterized by nucleus-independent chemical shift (NICS) values. The tautomer/isomer pair reference energies, from which the energies computed with PW6B95 are subtracted, correlate linearly with the corresponding differences in the NICS values. This correlation is used to construct a correction term for the pair energies computed with PW6B95, yielding tautomer/isomer pair energies with rmsd of 0.3 kcal/mol with respect to the more CPU time demanding QCISD(T)(quadruple-ζ) method. 相似文献