全文获取类型
收费全文 | 1492篇 |
免费 | 19篇 |
国内免费 | 4篇 |
出版年
2023年 | 2篇 |
2022年 | 3篇 |
2021年 | 5篇 |
2020年 | 40篇 |
2019年 | 83篇 |
2018年 | 81篇 |
2017年 | 63篇 |
2016年 | 56篇 |
2015年 | 29篇 |
2014年 | 124篇 |
2013年 | 155篇 |
2012年 | 98篇 |
2011年 | 175篇 |
2010年 | 113篇 |
2009年 | 59篇 |
2008年 | 41篇 |
2007年 | 55篇 |
2006年 | 61篇 |
2005年 | 49篇 |
2004年 | 31篇 |
2003年 | 37篇 |
2002年 | 11篇 |
2001年 | 5篇 |
2000年 | 4篇 |
1999年 | 8篇 |
1998年 | 3篇 |
1997年 | 8篇 |
1996年 | 16篇 |
1995年 | 12篇 |
1994年 | 10篇 |
1993年 | 8篇 |
1992年 | 8篇 |
1991年 | 2篇 |
1990年 | 5篇 |
1989年 | 2篇 |
1988年 | 2篇 |
1987年 | 3篇 |
1986年 | 2篇 |
1984年 | 7篇 |
1983年 | 5篇 |
1982年 | 5篇 |
1981年 | 3篇 |
1980年 | 6篇 |
1978年 | 3篇 |
1976年 | 6篇 |
1975年 | 3篇 |
1974年 | 2篇 |
1972年 | 1篇 |
1971年 | 1篇 |
1970年 | 1篇 |
排序方式: 共有1515条查询结果,搜索用时 31 毫秒
1.
Yifeng Yang Yingxiu Li Yunlei Hou Mingze Qin Ping Gong Ju Liu Yanfang Zhao 《Bioorganic & medicinal chemistry letters》2019,29(23):126666
A series of novel 4-phenoxyquinoline derivatives containing 3-oxo-3,4-dihydro-quinoxaline moiety were synthesized and evaluated for their antiproliferative activity against five human cancer cell lines (A549, H460, HT-29, MKN-45 and U87MG) in vitro. Most of the tested compounds exhibited more potent inhibitory activities than the positive control foretinib. Compound 1b, 1s and 1t were further examined for their inhibitory activity against c-Met kinase. The most promising compound 1s (with c-Met IC50 value of 1.42 nM) showed remarkable cytotoxicity against A549, H460, HT-29, MKN45 and U87MG cell lines with IC50 values of 0.39 μM, 0.18 μM, 0.38 μM, 0.81 μM, respectively. Their preliminary structure-activity relationships (SARs) study indicated that the replacement of the aromatic ring with the cyclohexane improved their antiproliferative activity. 相似文献
2.
Hao Zhang Xuejian Wang Jing Mao Yongxue Huang Wenfang Xu Yu Duan Jian Zhang 《Bioorganic & medicinal chemistry》2018,26(15):4363-4374
On the basis of the strategy of “multifunctional drugs”, a series of novel matrix metalloproteinase inhibitors (MMPIs) containing benzofuroxan scaffold as a nitric oxide donor were designed, synthesized and evaluated. All synthesized compounds, especially 16a, exhibited potent MMP-2,9 inhibitory activities, anti-proliferative activities and could produce high levels of NO in Hela cells. They were also evaluated for both of their anti-invasion and anti-angiogenesis effects. Furthermore, compared with LY52, 16a demonstrated competitive antitumor activity in vivo. These hybrid NO-MMPIs might offer suitable scaffolds to develop valuable MMP inhibitors for the further discovery of novel anti-cancer drugs. 相似文献
3.
Elizabeth Royall Nicole Doyle Azimah Abdul-Wahab Ed Emmott Simon J. Morley Ian Goodfellow Lisa O. Roberts Nicolas Locker 《The Journal of biological chemistry》2015,290(8):4748-4758
Protein synthesis is a tightly controlled process responding to several stimuli, including viral infection. As obligate intracellular parasites, viruses depend on the translation machinery of the host and can manipulate it by affecting the availability and function of specific eukaryotic initiation factors (eIFs). Human norovirus is a member of the Caliciviridae family and is responsible for gastroenteritis outbreaks. Previous studies on feline calicivirus and murine norovirus 1 (MNV1) demonstrated that the viral protein, genome-linked (VPg), acts to direct translation by hijacking the host protein synthesis machinery. Here we report that MNV1 infection modulates the MAPK pathway to activate eIF4E phosphorylation. Our results show that the activation of p38 and Mnk during MNV1 infection is important for MNV1 replication. Furthermore, phosphorylated eIF4E relocates to the polysomes, and this contributes to changes in the translational state of specific host mRNAs. We propose that global translational control of the host by eIF4E phosphorylation is a key component of the host-pathogen interaction. 相似文献
4.
《Bioorganic & medicinal chemistry letters》2014,24(10):2388-2391
In this study we report the synthesis and activity against bovine viral diarrhea virus (BVDV) of a novel series of bicycle δ-sultones containing γ-lactones. BVDV is responsible for major losses in cattle. Some of the synthesized δ-sultones showed pronounced anti-BVDV activity with EC50 values of 0.12–1.0 μM and no significant cytotoxicity. Among them, the ortho bromosubstituted derivative 4f (EC50 = 0.12 μM) showed better antiviral activity than other derivatives and was 10 fold more that of than positive control ribavirin (EC50 = 1.3 μM). BVDV is also considered to be a valuable surrogate for the hepatitis C virus (HCV) in antiviral drug studies. The above results provided a novel candidate for the development of anti-HCV agents. 相似文献
5.
《Bioorganic & medicinal chemistry letters》2014,24(4):1108-1110
A series of novel pazopanib derivatives, 7a–m, were designed and synthesized by modification of terminal benzene and indazole rings in pazopanib. The structures of all the synthesized compounds were confirmed by 1H NMR and MS. Their inhibitory activity against VEGFR-2, PDGFR-α and c-kit tyrosine kinases were evaluated. All the compounds exhibited definite kinase inhibition, in which compound 7l was most potent with IC50 values of 12 nM against VEGFR-2. Furthermore, compounds 7c, 7d and 7m demonstrated comparable inhibitory activity against three tyrosine kinases to pazopanib, and compound 7f showed superior inhibitory effects than that of pazopanib. 相似文献
6.
Dibyendu Mondal Eric M. Koehn Jiajun Yao David F. Wiemer Amnon Kohen 《Bioorganic & medicinal chemistry》2018,26(9):2365-2371
Exocyclic olefin variants of thymidylate (dTMP) recently have been proposed as reaction intermediates for the thymidyl biosynthesis enzymes found in many pathogenic organisms, yet synthetic reports on these materials are lacking. Here we report two strategies to prepare the exocyclic olefin isomer of dTMP, which is a putative reaction intermediate in pathogenic thymidylate biosynthesis and a novel nucleotide analog. Our most effective strategy involves preserving the existing glyosidic bond of thymidine and manipulating the base to generate the exocyclic methylene moiety. We also report a successful enzymatic deoxyribosylation of a non-aromatic nucleobase isomer of thymine, which provides an additional strategy to access nucleotide analogs with disrupted ring conjugation or with reduced heterocyclic bases. The strategies reported here are straightforward and extendable towards the synthesis of various pyrimidine nucleotide analogs, which could lead to compounds of value in studies of enzyme reaction mechanisms or serve as templates for rational drug design. 相似文献
7.
8.
《Bioorganic & medicinal chemistry letters》2014,24(24):5597-5601
In the present study, a series of 3-benzylquinazolin-4(3H)-ones were synthesized and characterized. Their vasodilative effects were evaluated by wire myograph on isolated rat mesenteric arterial ring induced contraction with 60 mM KCl. The SAR of target compounds was discussed preliminarily. Among these compounds, 2a and 2c displayed potent vasodilatation action and could compete significantly the rat mesenteric arterial rings induced contraction with phenylephrine. Compounds 2a and 2c were further tested for their antihypertensive effects in SHR by oral administration. The results indicated that 2a and 2c could reduce significantly both diastolic and systolic blood pressure. Moreover, 2c displayed antihypertensive effect in a dose dependent manner, and could maintain the effects for 6 h at a dosage of 4.0 mg/kg. These findings suggest that the title compounds are novel vasodilative agents, representing a novel series of promising antihypertensive agents. 相似文献
9.
《Bioorganic & medicinal chemistry》2014,22(3):1139-1147
An efficient one-pot three enzymes strategy for chemoenzymatic synthesis of ADP-d-glycero-β-d-manno-heptose (ADP-d, d-heptose) was reported using chemically synthesized d, d-heptose-7-phosphate and the ADP-d, d-heptose biosynthetic enzymes HldE and GmhB. Moreover, the result of investigating substrate specificity of the kinase action of HldE revealed that HldE had highly restricted substrate specificity towards structurally modified heptose-7-phosphate analogs. 相似文献
10.
《Bioorganic & medicinal chemistry》2020,28(16):115606
The emergence of multidrug resistant microorganisms has triggered the impending need for new aitimicrobial strategies. The antivirulence strategy with the benefite of alleviating the drug resistance becomes the focus of research. In this study, 22 quorum sensing inhibitors were synthesized by mimicking the structure of autoinducer and acinetobactin and up to 34% biofilm inhibition was observed with 5u. The biofilm inhibition effect was further demonstrated with extracellular polysaccharides inhibition and synergism with Gentamycin sulphate. 相似文献