全文获取类型
收费全文 | 1774篇 |
免费 | 59篇 |
国内免费 | 52篇 |
出版年
2023年 | 26篇 |
2022年 | 24篇 |
2021年 | 60篇 |
2020年 | 70篇 |
2019年 | 94篇 |
2018年 | 90篇 |
2017年 | 62篇 |
2016年 | 47篇 |
2015年 | 39篇 |
2014年 | 118篇 |
2013年 | 193篇 |
2012年 | 41篇 |
2011年 | 106篇 |
2010年 | 47篇 |
2009年 | 87篇 |
2008年 | 91篇 |
2007年 | 59篇 |
2006年 | 58篇 |
2005年 | 60篇 |
2004年 | 64篇 |
2003年 | 28篇 |
2002年 | 34篇 |
2001年 | 14篇 |
2000年 | 23篇 |
1999年 | 38篇 |
1998年 | 19篇 |
1997年 | 28篇 |
1996年 | 20篇 |
1995年 | 16篇 |
1994年 | 17篇 |
1993年 | 21篇 |
1992年 | 22篇 |
1991年 | 22篇 |
1990年 | 23篇 |
1989年 | 9篇 |
1988年 | 10篇 |
1987年 | 11篇 |
1986年 | 6篇 |
1985年 | 12篇 |
1984年 | 18篇 |
1983年 | 11篇 |
1982年 | 11篇 |
1981年 | 11篇 |
1980年 | 7篇 |
1979年 | 3篇 |
1978年 | 3篇 |
1976年 | 2篇 |
1975年 | 2篇 |
1974年 | 1篇 |
1973年 | 5篇 |
排序方式: 共有1885条查询结果,搜索用时 281 毫秒
51.
V.P. Greer P. Mason A.J. Kirby P.J. Nicholls C. Simons 《Journal of enzyme inhibition and medicinal chemistry》2013,28(5):431-443
In a search for novel inhibitors of RA-metabolising enzyme inhibitors as potential anti-cancer agents some 1,2-ethandiones, 2-hydroxyethanones and 1-ethylenedioxyethanones based on aryl-substituted 1,2-diphenylethane have been examined. Several of the compounds were weak inhibitors of the non-specific rat liver microsomal P450 enzymes and moderate inhibitors of the RA-induced enzymes in cultured human genital fibroblasts, where the RA-specific enzyme CYP26 is probably expressed. The 2-hydroxyethanone (13) with a 1-(4-dimethylaminophenyl) substituent was overall the most potent compound for rat liver microsomal enzyme (IC50=52.1?μM; ketoconazole, 2.8?μM) and the RA-induced enzyme (100?μM, 65.9% inhibition; ketoconazole, 20?μM, 75.0%). Modification of the dimethylamino group in (13) with more hydrophobic dialkylamino functions or separate modification of the 2-(2,4-dichlorophenyl) function did not improve potency. 相似文献
52.
B. K. Sharma P. Singh R. Kumar Susheela Sharma 《Journal of enzyme inhibition and medicinal chemistry》2013,28(1):50-55
Abstract GPR119 is a promising target for discovery of anti-type 2 diabetes mellitus agents. We described the optimisation of a novel series of pyrimido[5,4-b][1,4]oxazine derivatives as GPR119 agonists. Most designed compounds exhibited good agonistic activities. Among them, compound 10 and 15 demonstrated the potent EC50 values (13 and 12?nM, respectively) and strong inherent activities. Moreover, significant hypoglycaemic effect of compound 15 was observed by reducing the blood glucose AUC0–2h at the dose of 30?mg/kg, which is stronger than Vildagliptin (23.4% reduction vs. 17.9% reduction). 相似文献
53.
Vanessa Desplat Ambre Geneste Marc-Antoine Begorre Solene Belisle Fabre Stephane Brajot Stephane Massip 《Journal of enzyme inhibition and medicinal chemistry》2013,28(5):648-658
Akt kinases are attractive targets for small molecule drug discovery because of their key role in tumor cell survival/proliferation and their overexpression/activation in many human cancers. Recent efforts in the development and biological evaluation of small molecule inhibitors of Akt have led to the identification of novel Akt kinase inhibitors, based on a quinoxaline or pyrazinone scaffold. A series of new substituted pyrrolo[1,2-a]quinoxaline derivatives, structural analogues of these active quinoxaline or pyrazinone pharmacophores, was synthesized from various substituted 2-nitroanilines or 1,2-phenylenediamine via multistep heterocyclization process. These new compounds were tested for their in vitro ability to inhibit the proliferation of the human leukemic cell lines K562, U937 and HL60, and the breast cancer cell line MCF7. Three of these human cell lines (K562, U937 and MCF7) exhibited an active phosphorylated Akt form. The most promising active pyrroloquinoxalines were found to be 1a that inhibited K562 cell line proliferation with an IC50 of 4.5 μM, and 1h that inhibited U937 and MCF7 cell lines with IC50 of 5 and 8 μM, respectively. These two candidates exhibited more potent activities than the reference inhibitor A6730. 相似文献
54.
New inhibitors of fungal 17β-hydroxysteroid dehydrogenase based on the [1,5]-benzodiazepine scaffold
Matej Živec Matej Sova Mojca Brunskole Roman Lenaršič Tea Lanišnik Rižner Stanislav Gobec 《Journal of enzyme inhibition and medicinal chemistry》2013,28(1):29-36
The synthesis and activity of a new series of non-steroidal inhibitors of 17β-hydroxysteroid dehydrogenase that are based on a 1,5-benzodiazepine scaffold are presented. Their inhibitory potential was screened against 17β-hydroxysteroid dehydrogenase from the fungus Cochliobolus lunatus (17β-HSDcl), a model enzyme of the short-chain dehydrogenase/reductase superfamily. Some of these compounds are potent inhibitors of 17β-HSDcl activity, with IC50 values in the low micromolar range and represent promising lead compounds that should be further developed and investigated as inhibitors of human 17β-HSD isoforms, which are the enzymes associated with the development of many hormone-dependent and neuronal diseases. 相似文献
55.
Mikhail Krasavin Raivis Žalubovskis Aiga Grandāne Ilona Domračeva Petr Zhmurov 《Journal of enzyme inhibition and medicinal chemistry》2013,28(1):506-510
Abstract The hypothesis that sulfocoumarin acting as inhibitors of human carbonic anhydrase (CA, EC 4.2.1.1) cancer-associated isoforms hCA IX and – hCA XII is being able to also inhibit thioredoxin reductase was verified and confirmed. The dual targeting of two cancer cell defence mechanisms, i.e. hypoxia and oxidative stress, may both contribute to the observed antiproliferative profile of these compounds against many cancer cell lines. This unprecedented dual anticancer mechanism may lead to a new approach for designing innovative therapeutic agents. 相似文献
56.
《Nucleosides, nucleotides & nucleic acids》2013,32(12):2195-2202
Abstract 3′-C-Trifluoromethyl-β-D-ribonucleoside derivatives bearing the five naturally occurring nucleic acid bases have been synthesized. All these derivatives were prepared by glycosylation reactions of purine and pyrimidine bases with a suitable peracylated 3-C-trifluoromethyl ribofuranose precursor. After deprotection, the resulting title nucleoside analogues were tested for their inhibitory properties against the replication of HIV, HBV and several RNA viruses. However, none of these compounds showed significant antiviral activity. 相似文献
57.
58.
《Nucleosides, nucleotides & nucleic acids》2013,32(5-8):623-627
Abstract Preparation of the nucleoside analogues 1 and incorporation of 1, B = T, in deoxyribooligonucleotides by the phosphoramidite method is described. A two-step deprotection procedure was developed to reduce cleavage of the modified allylic unit. The binding properties of the modified oligonucleotides towards complementary DNA and RNA has been evaluated by Tm measurements showing a ΔTm of ?2 to ?6.5°C per modification. An oligonucleotide with two modifications at the 3′-end showed considerable resistance towards cleavage by a 3′-exonuclease. No antiviral activity against HIV-1 or HSV-1 was found for 1, B = G or T, or for any of the trihydroxy derivatives 5. 相似文献
59.
Novel syntheses of 4′-modified cyclopentenyl pyrimidine C-nucleosides were performed via C-C bond formation using SN2 alkylation via the key intermediate mesylates 6 and 16, which were prepared from acyclic ketone derivatives. When antiviral evaluation of synthesized compound was performed against various viruses such as HIV-1, HSV-1 and HSV-2, isocytidine analogue 20 showed moderate anti-HIV activity in CEM cell line (EC50 = 13.1 μmol).7 相似文献
60.
Matteo Tiecco Pietro Di Profio Raimondo Germani Gianfranco Savelli 《Nucleosides, nucleotides & nucleic acids》2013,32(10):911-923
Here we describe uridine functionalization in the 5′ position, which provides new classes of cationic and nonionic amphiphiles specifically designed as DNA transfection agents. The synthetic procedures developed to obtain the cationic uridine-head surfactants prevented intramolecular cyclization that occurs when uridine is functionalized in this position without using protecting groups in the uracil. 相似文献