全文获取类型
收费全文 | 26472篇 |
免费 | 1099篇 |
国内免费 | 894篇 |
出版年
2023年 | 359篇 |
2022年 | 537篇 |
2021年 | 609篇 |
2020年 | 569篇 |
2019年 | 797篇 |
2018年 | 824篇 |
2017年 | 523篇 |
2016年 | 560篇 |
2015年 | 618篇 |
2014年 | 1396篇 |
2013年 | 2126篇 |
2012年 | 932篇 |
2011年 | 1466篇 |
2010年 | 933篇 |
2009年 | 1236篇 |
2008年 | 1290篇 |
2007年 | 1288篇 |
2006年 | 1193篇 |
2005年 | 1153篇 |
2004年 | 984篇 |
2003年 | 878篇 |
2002年 | 771篇 |
2001年 | 508篇 |
2000年 | 465篇 |
1999年 | 495篇 |
1998年 | 445篇 |
1997年 | 393篇 |
1996年 | 383篇 |
1995年 | 417篇 |
1994年 | 328篇 |
1993年 | 294篇 |
1992年 | 270篇 |
1991年 | 255篇 |
1990年 | 195篇 |
1989年 | 192篇 |
1988年 | 185篇 |
1987年 | 178篇 |
1986年 | 151篇 |
1985年 | 254篇 |
1984年 | 316篇 |
1983年 | 223篇 |
1982年 | 251篇 |
1981年 | 218篇 |
1980年 | 186篇 |
1979年 | 158篇 |
1978年 | 138篇 |
1977年 | 116篇 |
1976年 | 109篇 |
1975年 | 72篇 |
1973年 | 72篇 |
排序方式: 共有10000条查询结果,搜索用时 21 毫秒
991.
Timothy A. Swearengin Eugene E. Fibuch Norbert W. Seidler 《Journal of enzyme inhibition and medicinal chemistry》2013,28(5):575-579
The mechanism of inhalation anesthesia remains to be fully elucidated. While certain neuronal membrane proteins are considered sites of action, cytosolic proteins may also be targets. We hypothesize that inhaled anesthetics may act via glyceraldehyde 3-phosphate dehydrogenase (GAPDH), which has recently been shown to participate in neuronal inhibition. We examined the effects of sevoflurane, a halogenated ether anesthetic, on the catalytic and fluorescence properties of GAPDH. Initial rates of oxidoreductase activity decreased approximately 30% at saturating levels of sevoflurane. NADH-stimulated oxidoreductase activity (25 μM NADH; 0.8 mM NAD+) increased with sevoflurane. Sevoflurane quenched tryptophan fluorescence emission and increased polarization. Additionally, sevoflurane increased the susceptibility of GAPDH to thermal denaturation suggesting an effect on conformation. Our findings warrant further research on sevoflurane's effect on GAPDH and indicate that this approach may lead to delineation of a novel contribution to the mechanism of anesthesia. 相似文献
992.
《Journal of enzyme inhibition and medicinal chemistry》2013,28(4):685-689
This study was designed to investigate the mushroom tyrosinase inhibitory activity for the constituents isolated from Neolitsea aciculata. The stems of N. aciculata was extracted with aqueous ethanol and subjected to chromatographic separation, which led to the isolation of 11 compounds: methyl linoleate (1), catechin (2), epicatechin (3), afzelin-7-O-glucopyranoside (4), 2′,3′-di-(p-coumaroyl)afzelin (5), 2′-p-coumaroylafzelin (6), feruloyl tyramine (7), β-sitosterol (8), daucosterol (9), oleic acid (10), and trilaurin (11). Their structures were elucidated on the basis of spectroscopic studies as well as by comparison with the data available in the literature. Among these isolates, compounds 5 and 6 were identified as potent mushroom tyrosinase inhibitors with IC50 values of 0.067 and 0.080 mM, respectively. The inhibition kinetics, analysed by Lineweaver–Burk plots, indicated that compounds 5 and 6 are competitive tyrosinase inhibitors when using l-tyrosine as a substrate. Notably, compounds 1–11 were isolated for the first time from this plant. These results provide evidence that this plant might be a potential source of anti-melanogenesis agents. 相似文献
993.
《Journal of enzyme inhibition and medicinal chemistry》2013,28(2):402-406
In this study, we have synthesised (3,4-dihydroxyphenyl)(2,3,4-trihydroxyphenyl)methanone and a series of its derivatives (5, 13–16) and tested the ability of these compounds to inhibit two metalloenzyme human carbonic anhydrase (hCA, EC 4.2.1.1) isozymes, hCA I and hCA II. The synthesised compounds showed inhibitory effect on hCA I and hCA II isozymes. The results showed that synthesised compounds (5, 13–16) demonstrated the best inhibition activity against hCA I (IC50: 3.22–54.28 μM) and hCA II (IC50: 18.52–142.01 μM). The compound 14 showed the highest inhibiton effect against hCA I (IC50: 3.22 μM; Ki: 1.19?±?1.4 μM). On the other hand, the compound 13 showed the highest inhibiton effect against hCA II (IC50: 18.52 μM; Ki: 3.25?±?1.13 μM). 相似文献
994.
《Journal of enzyme inhibition and medicinal chemistry》2013,28(3):565-568
Fatty acid synthase (FAS) has been proposed to be a new drug target for the development of anticancer agents because of the significant difference in expression of FAS between normal and tumour cells. Since a n-hexane-soluble extract from Ginkgo biloba was demonstrated to inhibit FAS activity in our preliminary test, we isolated active compounds from the n-hexane-soluble extract and evaluated their cytotoxic activity in human cancer cells. Three ginkgolic acids 1–3 isolated from the n-hexane-soluble extract inhibited the enzyme with IC50 values 17.1, 9.2 and 10.5 µM, respectively, and they showed cytotoxic activity against MCF-7 (human breast adenocarcinoma), A549 (human lung adenocarcinoma) and HL-60 (human leukaemia) cells. Our findings suggest that alkylphenol derivatives might be a new type of FAS inhibitor with cytotoxic activity. 相似文献
995.
《Journal of enzyme inhibition and medicinal chemistry》2013,28(6):812-817
A series of benzoic acid derivatives 1–10 have been synthesised by two different methods. Compounds 1–6 were synthesised by a facile procedure for esterification using N,N’-dicyclohexylcarbodiimide (DCC) as a coupling agent, methylene chloride as a solvent system and dimethylaminopyridine (DMAP). While 7–10 were synthesised by converting benzoic acid into benzoyl chloride by treating with thionyl chloride in the presence of benzene and performing a further reaction with amine in dried benzene. The structures of all the synthesised derivatives of benzoic acid (1–10) were assigned on the basis of extensive NMR studies. All of them showed inhibitory potential against tyrosinase. Among them, compound 7 was found to be the most potent (1.09 μM) when compared with the standard tyrosinase inhibitors of kojic acid (16.67 μM) and L-mimosine (3.68 μM). Finally in this paper, we have discussed the structure–activity relationships of the synthesised molecules. 相似文献
996.
《Journal of enzyme inhibition and medicinal chemistry》2013,28(6):547-556
AbstractIn this study the authors attempt to correlate kinetic constants for carbamylation of AChE, by a series of carbamate inhibitors, with the conformational positioning of Trp84 in transition state complexes of the same carbamates with Torpedo AChE, as obtained by computerized molecular modelling. They present evidence for changes in the distance of the carbamates from the center of the indole ring which can be correlated with the bimolecular rate constants for inhibition. As a result the greater the distance from Trp84, the smaller the bimolecular inhibition constant value, k1 (= k2/Ka), becomes. In conclusion, the value of the biinolecular rate constant for selected AChE inhibitors (structural changes that have been hypothesised or natural alkaloids of unknown activity) which possess similar size and rigidity, can be obtained. Under these conditions energy minimization alone seems to be sufficient even to accurately predict protein-substrate interactions that actually occur. Modelling studies also suggest that conformational re-orientation of Trp84 in the transition state could produce an overall movement of the Cys67-Cys94 loop. 相似文献
997.
Deniz Ekİncİ Şükrü Beydemir Ö. İrfan Küfrevİoğlu 《Journal of enzyme inhibition and medicinal chemistry》2013,28(6):745-750
The inhibition of two human carbonic anhydrase (HCA, EC 4.2.1.1) isozymes, the cytosolic HCA I and II, with heavy metal salts of Pb(II), Co(II) and Hg(II)has been investigated. Human erythrocyte CA-I isozyme was purified with a specific activity of 920 EUmg? 1 and a yield of 30% and CA-II isozyme was purified with a specific activity of 8000 EUmg? 1 and a yield of 40% using Sepharose-4B-L tyrosine-sulfanilamide affinity gel chromatography. The overall purification was approximately 104-fold for HCA-I and 900-fold for HCA-II. The inhibitory effects of different heavy metals (lead, cobalt and mercury) on CA activity were determined at low concentrations using the esterase method under in vitro conditions. Ki values for these metals were calculated from Lineweaver-Burk graphs as 1.0, 3.22 and 1.45 mM for HCA-I and 0.059, 1.382 and 0.32 mM for HCA-II respectively. Lead was a noncompetitive inhibitor for HCA-I and competitive for HCA-II, cobalt was competitive for HCA-I and noncompetitive for HCA-II and mercury was uncompetitive for both HCA-I and HCA-II. Lead was the best inhibitor for both HCA-I and HCA-II. 相似文献
998.
Mirosława Kot 《Journal of enzyme inhibition and medicinal chemistry》2013,28(6):697-701
p-Benzoquinone (pBQ) was studied as an inhibitor of jack bean urease in 20 mM phosphate buffer, pH 7.0, 1 mM EDTA, 25 °C. The inhibition was carried out by the use of a preincubation procedure in the absence of substrate. The influence of the inhibitor concentration and the preincubation time on the enzyme activity was elucidated. It was found that increase in pBQ concentration resulted in a linear decrease of urease activity. The dependence of the enzyme activity on the preincubation time showed that the rate of inhibition rapidly decreased at the beginning of the process in order to achieve the constant value. The inhibition became time independent in the studied time range. This observation is characteristic of a slow binding mechanism of inhibition. The protective experiment proved that the urease active site is involved in the binding of pBQ. High effectiveness of thiol protectors against pBQ inhibition indicates the strategic role of the active site sulfhydryl group in the blocking process. There were two methods used for reactivation of pBQ-inhibited urease. The dilution of the urease-pBQ complex in urea solution did not result in a regain of enzyme activity. Alternatively, the addition of dithiothreitol into the urease-pBQ mixture caused the instant and efficient reactivation of the enzyme. The experiments showed that the nature of the urease-pBQ complex is irreversible but the application of a specific thiol reagent can release the active enzyme from the complex. 相似文献
999.
Pinar Bozkaya Sureyya Ölgen Tulay Çoban Dogu NebIoglu 《Journal of enzyme inhibition and medicinal chemistry》2013,28(3):319-325
The antioxidant role of novel N-substituted indole-2-carboxamides (I2CDs) was investigated for their inhibitory effects on superoxide anion (O2? ) and lipid peroxidation (LP). Among the synthesized I2CDs, 3, 4, 6, 8 and 9 significantly inhibited O2· ? with an inhibition range at 70–98%. Examination of substituent effects on activity showed that both the ortho- and para-positions of the benzamide residue needs to be dichlorinated in order to get a maximum inhibitory effect on superoxide anion. In general, halogenated derivatives were found more active then the non-halogenated ones. However, none of the I2CDs had a significant inhibitory effects on the level of lipid peroxidation; only compounds 7 and 10 moderately decreased LP levels by over 50% at 10? 3 M concentrations. 相似文献
1000.
《Journal of enzyme inhibition and medicinal chemistry》2013,28(5):1054-1060
The aspartic protease inhibitory efficiency of rBm-33, an aspin from a filarial parasite Brugia malayi was investigated. rBm-33 was found to be thermostable up to 90°C and it forms a stable ‘enzyme-product’ complex with human pepsin. Aspartic protease inhibitory activity was investigated using UV spectroscopy and isothermal titration calorimetry. Our results suggest that rBm-33 inhibits the activity of important human aspartic proteases that were examined with binding constants (Kb) values between 10.23?×?103 and 6.52?×?103 M?1. The binding reactions were enthalpy driven with ΔHb values between ?50.99 and ?46.07 kJ mol?1. From kinetic studies, pepsin inhibition by rBm-33 was found to be linear competitive with an inhibition constant (Ki) of 2.5 (±0.8) nM. Because of the inhibitory efficacy of Bm-33 against important human aspartic proteases which play a vital role in immune-regulation along with other functions, Bm-33 can be projected as a drug target for the filariasis. 相似文献