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991.
Juan Sun Ming-Hui Li Shao-Song Qian Feng-Jiao Guo Xiao-Fang Dang Xiao-Ming Wang Ya-Rong Xue Hai-Liang Zhu 《Bioorganic & medicinal chemistry letters》2013,23(10):2876-2879
A series of 1,3,4-oxadiazole derivatives containing 1,4-benzodioxan moiety (7a–7q) have been designed, synthesized and evaluated for their antitumor activity. Most of the synthesized compounds were proved to have potent antitumor activity and low toxicity. Among them, compound 7a showed the most potent biological activity against Human Umbilical Vein Endothelial cells, which was comparable to the positive control. The results of apoptosis and flow cytometry (FCM) demonstrated that compound 7a induce cell apoptosis by the inhibition of MetAP2 pathway. Molecular docking was performed to position compound 7a into MetAP2 binding site in order to explore the potential target. 相似文献
992.
Zhongli Gao William J. Hurst Etienne Guillot Werngard Czechtizky Ulrike Lukasczyk Raisa Nagorny Marie-Pierre Pruniaux Lothar Schwink Juan Antonio Sanchez Siegfried Stengelin Lei Tang Irvin Winkler James A. Hendrix Pascal G. George 《Bioorganic & medicinal chemistry letters》2013,23(11):3416-3420
A series of structurally novel aryl ureas was derived from optimization of the HTS lead as selective histamine H3 receptor (H3R) antagonists. The SAR was explored and the data obtained set up the starting point and foundation for further optimization. The most potent tool compounds, as exemplified by compounds 2l, 5b, 5d, and 5e, displayed antagonism potencies in the subnanomolar range in in vitro human-H3R FLIPR assays and rhesus monkey H3R binding assays. 相似文献
993.
Horrick Sharma Tino W. Sanchez Nouri Neamati Mervi Detorio Raymond F. Schinazi Xiaolin Cheng John K. Buolamwini 《Bioorganic & medicinal chemistry letters》2013,23(22):6146-6151
In the present study we report the synthesis of halogen-substituted phenanthrene β-diketo acids as new HIV-1 integrase inhibitors. The target phenanthrenes were obtained using both standard thermal- and microwave-assisted synthesis. 4-(6-Chlorophenanthren-2-yl)-2,4-dioxobutanoic acid (18) was the most active compound of the series, inhibiting both 3′-end processing (3′-P) and strand transfer (ST) with IC50 values of 5 and 1.3 μM, respectively. Docking studies revealed two predominant binding modes that were distinct from the binding modes of raltegravir and elvitegravir, and suggest a novel binding region in the IN active site. Moreover, these compounds are predicted not to interact significantly with some of the key amino acids (Q148 and N155) implicated in viral resistance. Therefore, this series of compounds can further be investigated for a possible chemotype to circumvent resistance to clinical HIV-1 IN inhibitors. 相似文献
994.
Xianwen Cao Jing Jiang Shoude Zhang Lili Zhu Juan Zou Yanyan Diao Weilie Xiao Lei Shan Handong Sun Weidong Zhang Jin Huang Honglin Li 《Bioorganic & medicinal chemistry letters》2013,23(11):3329-3333
Eleven compounds were identified as estrogen receptor modulators from an in-house natural product database (NPD) by structure-based virtual screening for ERα and ERβ. Among them, 3 compounds were confirmed as ER agonists and 8 compounds were confirmed as ER antagonists by yeast two-hybrid (Y2H) assay, with EC50 values ranging from several micromolar to 100 micromolar. In this study, a novel series of cycloartane triterpenoids isolated from Schisandra glaucescens Diels was found to have ER antagonistic effect, the most potent antagonist of which exhibited activity with EC50 value of 2.55 and 4.68 μM for ERα and ERβ, respectively. Moreover, the types of modulation and subtype selectivity were also investigated through molecular docking simulation. 相似文献
995.
Maria Maddalena Cavalluzzi Maurizio Viale Claudio Bruno Alessia Carocci Alessia Catalano Antonio Carrieri Carlo Franchini Giovanni Lentini 《Bioorganic & medicinal chemistry letters》2013,23(17):4820-4823
Lubeluzole, a neuroprotective anti-ischemic drug, and its enantiomer were prepared following a convenient procedure based on hydrolytic kinetic resolution. The ee values were >99% and 96%, respectively, as assessed by HPLC analysis. The chemosensitizing effects of both enantiomers were evaluated in combination with either doxorubicin (human ovarian adenocarcinoma A2780 cells) or paclitaxel (human lung carcinoma A549 cells) by the MTT assay. At the lowest concentrations used, lubeluzole showed an overall and remarkable tendency to synergize with both anticancer drugs. In ovarian cancer cells a clear prevalence of antagonistic effect was observed for the R-enantiomer. The synergistic effects of lubeluzole for both drugs were observed over a wide concentration window (0.005–5 μM), the lowest limit being at least 40 times lower than human plasma concentrations previously reported as causing serious side effects. 相似文献
996.
Marco Antonio Natal Vigilato Alfonso Clavijo Terezinha Knobl Hugo Marcelo Tamayo Silva Ottorino Cosivi Maria Cristina Schneider Luis Fernando Leanes Albino José Belotto Marcos Antonio Espinal 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2013,368(1623)
Human rabies transmitted by dogs is considered a neglected disease that can be eliminated in Latin America and the Caribbean (LAC) by 2015. The aim of this paper is to discuss canine rabies policies and projections for LAC regarding current strategies for achieving this target and to critically review the political, economic and geographical factors related to the successful elimination of this deadly disease in the context of the difficulties and challenges of the region. The strong political and technical commitment to control rabies in LAC in the 1980s, started with the regional programme coordinated by the Pan American Health Organization. National and subnational programmes involve a range of strategies including mass canine vaccination with more than 51 million doses of canine vaccine produced annually, pre- and post-exposure prophylaxis, improvements in disease diagnosis and intensive surveillance. Rabies incidence in LAC has dramatically declined over the last few decades, with laboratory confirmed dog rabies cases decreasing from approximately 25 000 in 1980 to less than 300 in 2010. Dog-transmitted human rabies cases also decreased from 350 to less than 10 during the same period. Several countries have been declared free of human cases of dog-transmitted rabies, and from the 35 countries in the Americas, there is now only notification of human rabies transmitted by dogs in seven countries (Bolivia, Peru, Honduras, Haiti, Dominican Republic, Guatemala and some states in north and northeast Brazil). Here, we emphasize the importance of the political commitment in the final progression towards disease elimination. The availability of strategies for rabies control, the experience of most countries in the region and the historical ties of solidarity between countries with the support of the scientific community are evidence to affirm that the elimination of dog-transmitted rabies can be achieved in the short term. The final efforts to confront the remaining obstacles, like achieving and sustaining high vaccination coverage in communities that are most impoverished or in remote locations, are faced by countries that struggle to allocate sufficient financial and human resources for rabies control. Continent-wide cooperation is therefore required in the final efforts to secure the free status of remaining countries in the Americas, which is key to the regional elimination of human rabies transmitted by dogs. 相似文献
997.
Cristina M. Crava Yolanda Bel Agata K. Jakubowska Juan Ferré Baltasar Escriche 《Insect biochemistry and molecular biology》2013,43(10):924-935
Aminopeptidase N (APN) isoforms from Lepidoptera are known for their involvement in the mode of action of insecticidal Cry proteins from Bacillus thuringiensis. These enzymes belong to a protein family with at least eight different members that are expressed simultaneously in the midgut of lepidopteran larvae. Here, we focus on the characterization of the APNs from Ostrinia nubilalis (OnAPNs) to identify potential Cry receptors. We expressed OnAPNs in insect cells using a baculovirus system and analyzed their enzymatic activity by probing substrate specificity and inhibitor susceptibility. The interaction with Cry1Ab and Cry1Fa proteins (both found in transgenic insect-resistant maize) was evaluated by ligand blot assays and immunocytochemistry. Ligand blots of brush border membrane proteins showed that both Cry proteins bound mainly to a 150 kDa-band, in which OnAPNs were greatly represented. Binding analysis of Cry proteins to the cell-expressed OnAPNs showed that OnAPN1 interacted with both Cry1Ab and Cry1Fa, whereas OnAPN3a and OnAPN8 only bound to Cry1Fa. Two isoforms, OnAPN2 and OnAPN3b, did not interact with any of these two proteins. This work provides the first evidence of a differential role of OnAPN isoforms in the mode of action of Cry proteins in O. nubilalis. 相似文献
998.
M. Dora Carrión Mariem Chayah Antonio Entrena Ana López Miguel A. Gallo Darío Acuña-Castroviejo M. Encarnación Camacho 《Bioorganic & medicinal chemistry》2013,21(14):4132-4142
In a preliminary article, we reported a series of 4,5-dihydro-1H-pyrazole derivatives as neuronal nitric oxide synthase (nNOS) inhibitors. Here we present the data about the inhibition of inducible nitric oxide synthase (iNOS) of these compounds. In general, we can confirm that these pyrazoles are nNOS selective inhibitors. In addition, taking these compounds as a reference, we have designed and synthesized a series of new derivatives by modification of the heterocycle in 1-position, and by introduction of electron-donating or electron-withdrawing substituents in the aromatic ring. These derivatives have been evaluated as nNOS and iNOS inhibitors in order to identify new compounds with improved activity and selectivity. Compound 3r, with three methoxy electron-donating groups in the phenyl moiety, is the most potent nNOS inhibitor, showing good selectivity nNOS/iNOS. 相似文献
999.
Lisa Dalla Via Aída N. García-Argáez Arianna Adami Silvia Grancara Pamela Martinis Antonio Toninello Daniela Belli Dell’Amico Luca Labella Simona Samaritani 《Bioorganic & medicinal chemistry》2013,21(22):6965-6972
A convenient synthetic route and the characterization of complexes trans-[PtCl2(L)(PPh3)] (L = Et2NH (2), (PhCH2)2NH (3), (HOCH2CH2)2NH) (4) are reported. The antiproliferative activity was evaluated on three human tumor cell lines. The investigation on the mechanism of action highlighted for the most active complex 4 the capacity to affect mitochondrial functions. In particular, both the induction of the mitochondrial permeability transition phenomenon and an aspecific membrane damage occurred, depending on concentration. 相似文献
1000.
Ana I. Sánchez Valentín Martínez-Barrasa Carolina Burgos Juan J. Vaquero Julio Alvarez-Builla Emma Terricabras Víctor Segarra 《Bioorganic & medicinal chemistry》2013,21(8):2370-2378
The latest scientific findings concerning PDE7 and PDE4 inhibition suggest that selective small-molecule inhibitors of both enzymes could provide a novel approach to treat a variety of immunological diseases. In this context, we describe a new series of quinazoline derivatives from quinazolin-4-thiones which include a substituted biphenyl fragment. Some of these compounds show inhibitory potencies at sub-micromolar levels against the catalytic domain of PDE7. 相似文献