全文获取类型
收费全文 | 108401篇 |
免费 | 1511篇 |
国内免费 | 1972篇 |
出版年
2024年 | 31篇 |
2023年 | 198篇 |
2022年 | 494篇 |
2021年 | 941篇 |
2020年 | 569篇 |
2019年 | 762篇 |
2018年 | 12395篇 |
2017年 | 11060篇 |
2016年 | 8099篇 |
2015年 | 1611篇 |
2014年 | 1567篇 |
2013年 | 1697篇 |
2012年 | 5638篇 |
2011年 | 14023篇 |
2010年 | 12705篇 |
2009年 | 8861篇 |
2008年 | 10540篇 |
2007年 | 11977篇 |
2006年 | 806篇 |
2005年 | 999篇 |
2004年 | 1369篇 |
2003年 | 1372篇 |
2002年 | 1040篇 |
2001年 | 502篇 |
2000年 | 379篇 |
1999年 | 254篇 |
1998年 | 165篇 |
1997年 | 156篇 |
1996年 | 130篇 |
1995年 | 110篇 |
1994年 | 109篇 |
1993年 | 116篇 |
1992年 | 122篇 |
1991年 | 137篇 |
1990年 | 60篇 |
1989年 | 62篇 |
1988年 | 58篇 |
1987年 | 45篇 |
1986年 | 22篇 |
1985年 | 27篇 |
1984年 | 30篇 |
1983年 | 32篇 |
1982年 | 9篇 |
1972年 | 246篇 |
1971年 | 274篇 |
1965年 | 13篇 |
1962年 | 24篇 |
1956年 | 5篇 |
1944年 | 12篇 |
1940年 | 10篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
951.
Mingzhang Gao Zenas Shi Min Wang Qi-Huang Zheng 《Bioorganic & medicinal chemistry letters》2013,23(7):1953-1956
Olanzapine and its precursor desmethyl-Olanzapine were synthesized from malononitrile, propionaldehyde, 1-fluoro-2-nitrobenzene, and substituted piperazine in 4, 4, 5, and 5 steps with 35%, 32%, 26%, and 32% overall chemical yield, respectively. [11C]Olanzapine was prepared from desmethyl-Olanzapine with [11C]CH3OTf through N-[11C]methylation and isolated by HPLC combined with solid-phase extraction (SPE) in 40–50% radiochemical yield based on [11C]CO2 and decay corrected to end of bombardment (EOB), with 370–740 GBq/μmol specific activity at EOB. The calculated Log P (C Log P) value of [11C]Olanzapine is 3.39. 相似文献
952.
Zhongli Gao William J. Hurst Etienne Guillot Raisa Nagorny Marie-Pierre Pruniaux James A. Hendrix Pascal G. George 《Bioorganic & medicinal chemistry letters》2013,23(14):4044-4047
This Letter describes the asymmetric synthesis of the four stereoisomers (8a–8d) of a potent and highly selective histamine H3 receptor (H3R) antagonist, 5-fluoro-2-methyl-N-[2-methyl-4-(2-methyl[1,3′]bipyrrolidinyl-1′-yl) phenyl]benzamide (1). The physico-chemical properties, in vitro H3R affinities and ADME of 8a–8d were determined. Stereoisomer 8c (2S,3′S) displayed superior in vitro H3R affinity over other three stereoisomers and was selected for further profiling in in vivo PK and drug safety. Compound 8c exhibited excellent PK properties with high exposure, desired brain to plasma ratio and reasonable brain half life. However, all stereoisomers showed similar unwanted hERG affinities. 相似文献
953.
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
954.
Zhen-Wei Wu Hai-Wei Xu Gui-Fu Dai Meng-Jiao Liu Li-Ping Zhu Jian Wu Ya-Nan Wang Feng-Juan Wu Dan Zhao Ming-Fu Gao Shan-Shan Nie Wei Han Jing-Hui Song Hong-Min Liu 《Bioorganic & medicinal chemistry letters》2013,23(23):6421-6426
In the present study, andrographolide (Andro, 1) derivatives were screened to identify potent inhibitors against tumor-cell migration and invasion, and associated structure–activity relationships were studied. Compared to 1, compounds 8a–8d exhibited more potent activities against migration in SGC-7901, PC-3, A549, HT-29 and Ec109 cell lines. Improved activities against tumor-cell migration and invasion were proved to be associated with the down-regulation of MMPs. 相似文献
955.
Jing Chen Cheng-Shi Jiang Wen-Quan Ma Li-Xin Gao Jing-Xu Gong Jing-Ya Li Jia Li Yue-Wei Guo 《Bioorganic & medicinal chemistry letters》2013,23(18):5061-5065
Bruguiesulfurol (1), a cyclic 4-hydroxy-dithiosulfonate isolated from mangrove plant Bruguiera gymnorrhiza, was concisely synthesized for the first time in four steps, and a series of its synthetic derivatives were evaluated for in vitro inhibitory effects on PTP1B and related PTPs. Some derivatives were found to have improved pharmacological profile compared with hit 1. Among them, 5a showed the potent selectivity towards PTP1B over other PTPs, including TCPTP, and 7j exhibited the strongest PTP1B inhibitory activity with an IC50 value of 4.54 μM. 相似文献
956.
Miaorong Huang Zicong Li Xiaoling Huang Wenchao Gao Cailin Zhu Hui Xu Yujuan Yuan Liang Shuai Ruiai Chen Zhenfang Wu Dewu Liu 《Transgenic research》2013,22(4):779-790
Cellulose is the main non-starch polysaccharides (NSP) in plant cell walls and acts as anti-nutritional factor in animal feed. However, monogastric animals do not synthesize enzymes that cleave such plant structural polysaccharides and thus waste of resources and pollute the environment. We described the vectors construction and co-expressions of a multi-functional cellulase EGX (with the activities of exo-β-1,4-glucanase, endo-β-1,4-glucanase, and endo-β-1,4-xylanase activities) from mollusca, Ampullaria crossean and a β-glucosidase BGL1 from Asperjillus niger in CHO cells and the transgenic mice. The recombinant enzymes were synthesised, secreted by the direction of pig PSP signal peptide and functionally active in the eukaryote systems including both of CHO cells and transgenic mice by RT-PCR analysis, western blot analysis and cellulolytic enzymes activities assays. Expressions were salivary glands-specific dependent under the control of pig PSP promoter in transgenic mice. 2A peptide was used as the self-cleaving sequence to mediate co-expression of the fusion genes and the cleavage efficiency was very high both in vitro and in vivo according to the western blot analysis. In summary, we have demonstrated that the single ORF containing EGX and BGL1 were co-expressed by 2A peptide in CHO cells and transgenic mice. It presents a viable technology for efficient disruption of plant cell wall and liberation of nutrients. To our knowledge, this is the first report using 2A sequence to produce multiple cellulases in mammalian cells and transgenic animals. 相似文献
957.
958.
Xiaoyan Pan Fang Wang Yanmin Zhang Hongping Gao Zhigang Hu Sicen Wang Jie Zhang 《Bioorganic & medicinal chemistry》2013,21(9):2527-2534
A novel class of Nilotinib derivatives, B1–B20, were synthesized in high yields using various substituted anilines. All the title compounds were evaluated for their inhibitory activities against Bcr–Abl and antiproliferative effects on human leukemia cell (K562). The pharmacological results indicated that some compounds exhibited promising anticancer activity. In particular, compound B14 containing tertiary amine side chain exhibited Bcr–Abl inhibitory activity similar to that of Nilotinib. It was suggested that the introduction of the tertiary amine moiety could improve Bcr–Abl inhibitory activity and antitumor effects. 相似文献
959.
Peiju Qiu Lingling Xu Lei Gao Meng Zhang Shixi Wang Sheng Tong Yue Sun Lijuan Zhang Tao Jiang 《Bioorganic & medicinal chemistry》2013,21(17):5012-5020
Epidermal growth factor receptor (EGFR) is an effective molecular target of anti-cancer therapies. Curcumin inhibits cancer cell growth in vitro by suppressing gene expression of EGFR and reduces tumor growth in various animal models. To overcome instable and insoluble properties of curcumin as therapeutics, we designed and synthesized six novel pyrimidine-substituted curcumin analogues with or without a hydroxyl group originally present in curcumin. The cell viability tests indicated that IC50 of the analogues containing hydroxyl group were 3 to 8-fold lower than those of the analogues without hydroxyl group in two colon cancer cell lines tested. Western blot analysis indicates the analogues containing hydroxyl group inhibited expression and tyrosine phosphorylation of EGFR. Further protein analyses showed that the analogues had anti-cellular proliferation, pro-apoptosis, and cell cycle arrest properties associated with suppressed EGFR expression. These results indicate that the hydroxyl groups in curcumin and the analogues were critical for observed biological activities. 相似文献
960.
麻疹病毒受体与病毒侵入 总被引:1,自引:0,他引:1
麻疹病毒是一种具囊膜的负链RNA病毒,两种主要的囊膜蛋白血凝素蛋白(H)和膜融合蛋白(F)表达在膜表面负责病毒侵入过程中与宿主受体的结合和膜融合过程.病毒囊膜蛋白与受体的相互作用是病毒侵入宿主的关键步骤,决定了病毒感染能力、种属和组织嗜性.因此,囊膜病毒与受体的结合位点往往成为重要的抗病毒药物的靶点.目前已发现的3种麻疹病毒受体包括CD46、SLAM和Nectin-4.以下综述了麻疹病毒受体的特征及在病毒侵入中的作用、麻疹病毒H蛋白与受体的相互作用机制,为抗病毒药物设计及麻疹病毒作为肿瘤治疗性载体的应用提供理论依据. 相似文献