全文获取类型
收费全文 | 7477篇 |
免费 | 315篇 |
国内免费 | 59篇 |
出版年
2024年 | 6篇 |
2023年 | 44篇 |
2022年 | 84篇 |
2021年 | 127篇 |
2020年 | 152篇 |
2019年 | 207篇 |
2018年 | 207篇 |
2017年 | 134篇 |
2016年 | 142篇 |
2015年 | 218篇 |
2014年 | 512篇 |
2013年 | 439篇 |
2012年 | 372篇 |
2011年 | 597篇 |
2010年 | 425篇 |
2009年 | 516篇 |
2008年 | 548篇 |
2007年 | 609篇 |
2006年 | 503篇 |
2005年 | 361篇 |
2004年 | 381篇 |
2003年 | 345篇 |
2002年 | 202篇 |
2001年 | 74篇 |
2000年 | 155篇 |
1999年 | 137篇 |
1998年 | 125篇 |
1997年 | 96篇 |
1996年 | 59篇 |
1995年 | 24篇 |
1994年 | 17篇 |
1993年 | 12篇 |
1992年 | 4篇 |
1991年 | 1篇 |
1990年 | 1篇 |
1989年 | 3篇 |
1988年 | 1篇 |
1987年 | 1篇 |
1986年 | 3篇 |
1984年 | 1篇 |
1983年 | 1篇 |
1980年 | 1篇 |
1979年 | 1篇 |
1978年 | 1篇 |
1975年 | 1篇 |
1973年 | 1篇 |
排序方式: 共有7851条查询结果,搜索用时 15 毫秒
121.
Meilan Huang Zhuo Li Dawei Li Steven Walker Caroline Greenan Richard Kennedy 《Bioorganic & medicinal chemistry letters》2013,23(10):3044-3050
We identified nine small-molecule hit compounds of Heat shock 70 kDa protein 5 (HSPA5) from cascade in silico screening based on the binding modes of the tetrapeptides derived from the peptide substrate or inhibitors of Escherichia coli HSP70. Two compounds exhibit promising inhibition activities from cancer cell viability and tumor inhibition assays. The binding modes of the hit compounds provide a platform for development of selective small molecule inhibitors of HSPA5. 相似文献
122.
Xiao-Chao Huang Meng Wang Ying-Ming Pan Xiao-Yan Tian Heng-Shan Wang Ye Zhang 《Bioorganic & medicinal chemistry letters》2013,23(19):5283-5289
A series of novel α-aminophosphonate derivatives containing DHA structure were designed and synthesized as antitumor agents. In vitro antitumor activities of these compounds against the NCI-H460 (human lung cancer cell), A549 (human lung adenocarcinoma cell), HepG2 (human liver cancer cell) and SKOV3 (human ovarian cancer cell) human cancer cell lines were evaluated and compared with commercial anticancer drug 5-fluorouracil (5-FU), employing standard MTT assay. The pharmacological screening results revealed that many compounds exhibited moderate to high levels of antitumor activities against the tested cancer cell lines and that most demonstrated more potent inhibitory activities compared with the commercial anticancer drug 5-FU. The action mechanism of representative compound 7c was preliminarily investigated by acridine orange/ethidium bromide staining, Hoechst 33258 staining, JC-1 mitochondrial membrane potential staining and flow cytometry, which indicated that the compound can induce cell apoptosis in NCI-H460 cells. Cell cycle analysis showed that compound 7c mainly arrested NCI-H460 cells in G1 stage. 相似文献
123.
Sandra Oramas-Royo Concepción Torrejón Irene Cuadrado Rita Hernández-Molina Sonsoles Hortelano Ana Estévez-Braun Beatriz de las Heras 《Bioorganic & medicinal chemistry》2013,21(9):2471-2477
In the present study, a series of metallic complexes of the 1,4-naphthoquinone lawsone (2–6) were synthesized and evaluated for potential cytotoxicity in a mouse leukemic macrophagic RAW 264.7 cell line. Cell viability was determined by the MTT assay. Significant growth inhibition was observed for the copper complex (4) with an IC50 value of 2.5 μM. This compound was selected for further evaluation of cytotoxic activity on several human cancer cells including HT-29 (human colorectal adenocarcinoma), HepG2 (human hepatocellular carcinoma) and HeLa, (human cervical adenocarcinoma cells). Significant cell viability decrease was also observed in HepG2 cells. The apoptotic potential of this complex was evaluated in these cells. Compound 4 induced apoptosis by a mechanism that involves the activation of caspases 3, 8 and 9 and modulation of apoptotic-related proteins such as Bax, Bad, and p53. These results indicate that metal complexes of lawsone derivatives, in particular compound 4, might be used for the design of new antitumoral agents. 相似文献
124.
David J. Richard Ryan Lena Thomas Bannister Noel Blake William E. Pierceall Nicole E. Carlson Christina Eberhart Keller Marcel Koenig Yuanjun He Dmitriy Minond Jitendra Mishra Michael Cameron Timothy Spicer Peter Hodder Michael H. Cardone 《Bioorganic & medicinal chemistry》2013,21(21):6642-6649
Anti-apoptotic Bcl-2 family proteins are important oncology therapeutic targets. To date, BH3 mimetics that abrogate anti-apoptotic activity have largely been directed at Bcl-2 and/or Bcl-xL. One observed mechanism of resistance to these inhibitors is increased Mcl-1 levels in cells exposed to such therapeutics. For this reason, and because Mcl-1 is important in the onset of lymphoid, myeloid, and other cancers, it has become a target of great interest. However, small molecule inhibitors displaying potency and selectivity for Mcl-1 are lacking. Identifying such compounds has been challenging due to difficulties in translating the target selectivity observed at the biochemical level to the cellular level. Herein we report the results of an HTS strategy coupled with directed hit optimization. Compounds identified have selective Mcl-1 inhibitory activity with greater than 100-fold reduced affinity for Bcl-xL. The selectivity of these compounds at the cellular level was validated using BH3 profiling, a novel personalized diagnostic approach. This assay provides an important functional biomarker that allows for the characterization of cells based upon their dependencies on various anti-apoptotic Bcl-2 proteins. We demonstrate that cells dependent on Mcl-1 or Bcl-2/Bcl-xL for survival are commensurately responsive to compounds that genuinely target those proteins. The identification of compound 9 with uniquely validated and selective Mcl-1 inhibitory activity provides a valuable tool to those studying the intrinsic apoptosis pathway and highlights an important approach in the development of a first-in-class cancer therapeutic. 相似文献
125.
Richard K. Amewu James Chadwick Afthab Hussain Somnath Panda Rinki Rinki Omar Janneh Stephen A. Ward Candel Miguel Hollie Burrell-Saward Livia Vivas Paul M. O’Neill 《Bioorganic & medicinal chemistry》2013,21(23):7392-7397
The synthesis of a range of mono spiro and dispiro 1,2,4,5-tetraoxane dimers is described. Selected molecules were examined in in vitro assays to determine their antimalarial and anticancer potential. Our studies reveal that several molecules possess potent nanomolar antimalarial and single digit micromolar antiproliferative IC50s versus colon (HT29-AK and leukemia (HL60) cell lines. 相似文献
126.
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
127.
Hai-xia Qin Jun Yang Hong-kai Cui Shao-ping Li Wei Zhang Xiao-li Ding Yong-hua Xia 《Cytotechnology》2013,65(4):643-653
A recent report showed that reversine treatment could induce murine myoblasts dedifferentiation into multipotent progenitor cells and inhibit proliferation of some tumors, and other reports showed that apoptosis of lung adenocarcinoma cells could be induced by aspirin. The aim of the present study was to evaluate the synergistic antitumor effects of reversine and aspirin on cervical cancer. The inhibition rate of reversine and aspirin on cervical cancer cell lines’ (HeLa and U14) was determined by MTT method, cell cycle of HeLa and U14 cells was analyzed by FACS, mitochondrial membrane potential of HeLa and U14 was detected using a JC-1 kit. HeLa and U14 colony formation was analyzed by soft agar colony formation assay. The expression of caspase-3, Bcl-2/Bax, cyclin D1 and p21 was detected by qRT-PCR and Western Blotting. Moreover, tumor weight and tumor volume was assessed using a murine model of cervical cancer with U14 cells subcutaneously (s.c.) administered into the neck, separately or combined with drug administration via the intraperitoneal (i.p.) route. The inhibition rate of cells in the combination group (10 μmol/L reversine, 10 mmol/L aspirin) increased significantly in comparison to that when the drugs were used alone (P < 0.05); moreover, this combination could synergistically inhibit the proliferation of five cervical cancer cell lines (HeLa, U14, Siha, Caski and C33A). In the therapeutic mouse model, tumor weight and tumor volume of cervical cancer bearing mice was more reduced when compared with the control agents (P < 0.05) in tumor-bearing mice. The combination of reversine and aspirin exerts synergistic growth inhibition and apoptosis induction on cervical cancers cells. 相似文献
128.
目的:探讨光敏剂(HMME)介导的光动力疗法对人骨肉瘤细胞U-2OS的杀伤效应及机制研究。方法:使用不同浓度(0、10、20、30、40μg.ml-1)的光敏剂,采用不同光照能量(0、3、6、9 J.cm-2)照射人骨肉瘤细胞,与空白对照组、药物对照组(无光照但加光敏剂)和光照对照组(不加光敏剂但加光照)进行比较,MTT法检测细胞的存活率,选择半数有效量药物浓度和光照能量,作为实验组。以空白对照组为对照,采用Hoechst33342染色法,观察细胞凋亡情况。用western blot方法检测细胞凋亡蛋白caspase-7、caspase-9和PARP-1。结果:MTT结果显示,空白对照组、药物对照组和光照对照组对细胞存活率在96.7%和100%之间,药物的半数有效量为40.1μg.ml-(16 J.cm-2)和25.0μg.ml-(19 J.cm-2)。Hoechst33342染色法观察到实验组细胞明显凋亡。westen blotting检测结果,实验组与对照组相比,caspase-7、caspase-9和PARP-1表达明显增高。结论:HMME-PDT对人骨肉瘤细胞U-2OS有显著的杀伤效应,且呈光敏剂浓度和光照强度依赖性,其杀伤效应与caspase途径相关。 相似文献
129.
目的:观察线粒体分裂蛋白抑制剂在大鼠脑缺血再灌注损伤中的作用,并初步探讨其在线粒体凋亡途径中的作用机制.方法:雄性Wistar大鼠48只,体重250~300 g,随机分为三组(n=16):假手术组(Sham组)、脑缺血再灌注组(I/R组)和mdivi-1预处理组(mdivi-1组),线栓法建立大鼠大脑中动脉闭塞(MCAO)模型,缺血2小时,再灌注24小时后应用流式细胞术检测神经元凋亡;Western blot法检测Cyt C蛋白的表达;RT-PCR法检测Cyt C mRNA的表达.结果:与Sham组比较,I/R组神经细胞凋亡率与CytC蛋白以及mRNA表达水平显著升高(P<0.01).应用mdivi-1预处理后细胞凋亡率与CytC蛋白以及mRNA表达水平明显降低(P<0.01).结论:线粒体分裂蛋白抑制剂可以明显减轻脑缺血再灌注损伤,其作用机制可能通过阻断线粒体-细胞色素C途径来抑制细胞凋亡. 相似文献
130.