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91.
Using pyridino[2,3-D]pyrimidine as the core, total 13 pyridino[2,3-D]pyrimidine derivatives with different alkyl substituents at C2 site have been designed and synthesized to search for novel PI3Kα/mTOR dual inhibitors. Most of the target compounds showed potent mTOR inhibition activity with IC50 values ranging from single to double digit nanomole. Five target compounds exhibited pronounced PI3Kα inhibition activity. In vitro cellular assay indicated that most of the target compounds showed excellent antiproliferative activity, especially 3j whose potency against SKOV3 was 8-fold higher than the positive control AZD8055. In vitro metabolic stability study found that 3j had a comparable stability to that of AZD8055. More importantly, 3j showed better antitumor activity and pharmacokinetic properties in vivo as compared with AZD8055. 相似文献
92.
Takuto Kojima Yasutomi Asano Osamu Kurasawa Yasuhiro Hirata Naoki Iwamura Tzu-Tshin Wong Bunnai Saito Yuta Tanaka Ryosuke Arai Kazuko Yonemori Yasufumi Miyamoto Yoji Sagiya Masahiro Yaguchi Sachio Shibata Akio Mizutani Osamu Sano Ryutaro Adachi Yoshinori Satomi Shinichi Imamura 《Bioorganic & medicinal chemistry》2018,26(9):2452-2465
We pursued serine palmitoyltransferase (SPT) inhibitors as novel cancer therapeutic agents based on a correlation between SPT inhibition and growth suppression of cancer cells. High-throughput screening and medicinal chemistry efforts led to the identification of structurally diverse SPT inhibitors 4 and 5. Both compounds potently inhibited SPT enzyme and decreased intracellular ceramide content. In addition, they suppressed cell growth of human lung adenocarcinoma HCC4006 and acute promyelocytic leukemia PL-21, and displayed good pharmacokinetic profiles. Reduction of 3-ketodihydrosphingosine, the direct downstream product of SPT, was confirmed under in vivo settings after oral administration of compounds 4 and 5. Their anti-tumor efficacy was observed in a PL-21 xenograft mouse model. These results suggested that SPT inhibitors might have potential to be effective cancer therapeutics. 相似文献
93.
Hao Li Fang Fang Yunqi Liu Liangmin Xue Meng Wang Ying Guo Xiaowei Wang Chao Tian Junyi Liu Zhili Zhang 《Bioorganic & medicinal chemistry》2018,26(9):2674-2685
Bridge homologation of the previously reported nonclassical two-carbon-bridged antifolate, 2,4-diamino-6-phenethylpyrido[3,2-d]pyrimidine (wm-5a), afforded the three-, four- and five-carbon-bridged antifolate analogues 3.1–3.5, 4.1–4.2 and 5.1–5.5. The target compounds, with substituents at various positions on the carbon bridges, were efficiently synthesized by aldol condensation or Wittig reaction and followed by reduction. Elongation of the two-carbon bridge to three-, four- or five-carbon bridges, and also saturation of the carbon bridges, provided compounds with good inhibitory activity against recombinant human DHFR (rhDHFR). Analogue 3.5, which has a three-carbon bridge, inhibited the proliferation of HL-60 and HCT116 cells to a greater extent than the other analogues. Compound 3.5 was also the most potent inhibitor of rhDHFR (IC50?=?0.06?μM), and was approximately 38-fold more potent than the two-carbon-bridged lead compound. Docking studies revealed that both the length and flexibility of the saturated carbon bridge in 3.5 were important for high potency. Flow cytometry studies indicated that compound 3.5 arrested HL-60 cells in the S-phase and induced apoptosis. Western blot analysis of HL-60 cells treated with 3.5 showed a dose-dependent upregulation of DHFR protein levels. 相似文献
94.
Lentinan, β-1,6;1,3-glucan, showing an antitumor effect against mouse solid type tumors, can induce marked vascular dilation
and hemorrhage (VDH) in very localized areas such as the ears, feet, and tails of mice in the early stages after its administration
(Maeda et al. 1984). VDH has been found to be one of the T-cell-mediated responses triggered by lentinan. We reported previously
that the responsiveness of mice to lentinan with respect to VDH induction is controlled by a dominant gene(s), Ltn2 (formerly), and that no sex difference was observed (Maeda et al. 1991). To determine the chromosomal location of the Ltn2 gene(s), we typed genomic DNAs of 193 N2 segregants of crosses between a high responder MA/MyJ and a low responder AKR/J by the polymerase chain reaction-simple sequence
length polymorphism technique using 83 chromosome-specific microsatellite markers. We identified one major gene (Ltnr3) and three minor genes (Ltnr4, Ltnr5, and Ltnr6) responsible for the VDH induction. Ltnr3 was closely linked to D6Mit135 on chromosome 6 (P <0.00000) and Ltnr4, Ltnr5, and Ltnr6 to D9Mit161 on chromosome 9 (P <0.00032), D15Mit147 on chromosome 15 (P <0.00014) and D16Mit4 on chromosome 16 (P <0.00014), respectively.
Received: 26 May 1997 / Revised: 3 September 1997 相似文献
95.
Josef Matoušek 《Comparative biochemistry and physiology. Toxicology & pharmacology : CBP》2001,129(3):175-191
The antitumor effect of ribonucleases was studied with animal ribonucleolytic enzymes, bovine pancreatic RNase A, bovine seminal RNase (BS-RNase), onconase and angiogenin. While bovine pancreatic RNase A exerts a minor antitumor effect, BS-RNase and onconase exert significant effects. Angiogenin, as RNase, works in an opposite way, it initiates vascularization of tumors and subsequent tumor growth. Ribonunclease inhibitors are not able to inhibit the antitumor effectiveness of BS-RNase or onconase. However, they do so in the case of pancreatic RNases. Conjugation of BS-RNase with antibodies against tumor antigens (preparation of immunotoxins) like the conjugation of the enzyme with polymers enhances the antitumor activity of the ribonuclease. After conjugation with polymers, the half-life of BS-RNase in blood is extended and its immunogenicity reduced. Recombinant RNases have the same functional activity as the native enzymes. The synthetic genes have also been modified, some of them with gene sequences typical for the BS-RNase parts. Recent experimental efforts are directed to the preparation of ‘humanized antitumor ribonuclease’ that would be structurally similar to human enzyme with minimal immunogenicity and side effects. The angiogenesis of tumors is attempted to be minimized by specific antibodies or anti-angiogenic substances. 相似文献
96.
Motomu Shimizu Yasutaka Takeda Hideo Yagita Takayuki Yoshimoto Akio Matsuzawa 《Cancer immunology, immunotherapy : CII》1998,47(3):143-148
Lymph node (LN) cells of Fas-mutant mice lpr/lpr (lpr) and lpr
cg
/lpr
cg
(lpr
cg
) express an increased level of Fas ligand (FasL) (CD95L). We examined the antitumor potential of cell-bound FasL on these
LN cells against Fas+ tumor cells. Fas+ F6b and Fas− N1d cells were produced from murine hepatoma MH134 (Fas−) by gene transfection. lpr and lpr
cg
LN cells inhibited growth of F6b but not N1d cells in vitro. Neither gld/gld lpr/lpr (gld/lpr) LN cells, which lack both FasL and Fas, nor wild-type LN cells showed growth-inhibitory activities against F6b and N1d cells.
The effector cells and molecule were CD4−CD8− T cells and FasL, respectively. The tumor neutralization test and adoptive transfer demonstrated that lpr and lpr
cg
, but not gld/lpr, LN cells retarded the growth of F6b cells. Although anti-Fas antibody and FasL cause severe liver failure, wild-type mice
injected with lpr LN cells appeared clinically normal. Adoptive transfer of lpr LN cells to F6b-bearing mice exerted the same antitumor activity in wild-type and gld/lpr recipient mice, indicating the applicability of cell-bound FasL for Fas-mediated target therapy of cancer. These results
suggest that antitumor activity was dependent on the Fas-FasL system and that lymphoid cells overexpressing FasL can be powerful
antitumor effector cells against Fas+ tumor cells.
Received: 16 March 1998 / Accepted: 28 July 1998 相似文献
97.
K. Tanaka Akira Yamada Kiyoshi Noda Takashi Hasegawa Masao Okuda Yukihiro Shoyama Kikuo Nomoto 《Cancer immunology, immunotherapy : CII》1998,45(6):313-320
A glycoprotein extract (CVS), derived from the unicellular green alga Chlorella vulgaris, strain CK22, exhibited a pronounced antitumor effect against both spontaneous and experimentally induced metastasis in mice.
Inhibition of tumor metastasis was enhanced when intratumor administration of CVS was followed by s.c. injection of CVS. Anti-metastatic
immunopotentiation was observed in euthymic mice, but not in athymic nude mice. The antitumor activity of CVS was reflected
in antigen-specific, T-cell-mediated immunity. Both CD4 and CD8 T cells contributed to the antimetastatic effects, as shown
by in vivo depletion experiments with anti-T-cell subset antibodies. Furthermore, CVS caused the recruitment of T cells to
the regional lymph nodes and their proliferation in these organs. The CD4-positive population, following CVS injection at
the time of tumor rechallenge, displayed a pronounced increase in the proportion of T cells that were CD18 bright, CD44 bright,
CD25+, CD54+, CD69+ or CD71+ in the lymph nodes. Thus, CVS induces T cell activation in peripheral lymph nodes in tumor-bearing mice. We conclude that
CVS augments antimetastatic immunity through T cell activation in lymphoid organs and enhances recruitment of these cells
to the tumor sites. Presurgical treatment with CVS might prevent metastasis or tumor progression.
Received: 5 June 1997 / Accepted: 12 September 1997 相似文献
98.
Valery Kudryashov Hyunjin M. Kim Govindaswami Ragupathi Samuel J. Danishefsky Philip O. Livingston K. O. Lloyd 《Cancer immunology, immunotherapy : CII》1998,45(6):281-286
Many human carcinomas overexpress the Lewisy (Ley) blood-group epitope [Fucα1→2Galβ1→4 (Fucα1→3)GlcNAcβ1→3Gal-]. With a view to developing Ley based vaccines we have examined the immunogenicity of Ley-protein conjugates in mice. Ley pentasaccharide was synthesized as its allyl glycoside and coupled to keyhole limpet hemocyanin (KLH) by reductive amination
or by a novel method utilizing a maleido-derivitized alkyl carboxyhydrazide as a bridging group to 2-iminothiolane-derivitized
KLH. Ley oligosaccharide was also coupled to bovine serum albumin by reductive amination. Immunization of groups of mice with the
three conjugates, together with the immunological adjuvant QS21, showed that Ley oligosaccharide directly coupled to KLH was the most efficient conjugate for eliciting IgG and IgM antibody responses to
naturally occurring forms of Ley epitopes carried on mucins and glycolipids. These antibodies were also reactive with and cytotoxic to a human breast cancer
cell line expressing Ley (MCF-7). These experiments suggest that Ley-KLH antigen and QS21 adjuvant could be considered as an immunogenic therapeutic vaccine in carcinoma patients.
Received: 28 March 1997 / Accepted: 2 September 1997 相似文献
99.
《Bioorganic & medicinal chemistry》2016,24(13):3043-3051
A series of 4-(thiazol-2-ylamino)-benzenesulfonamides was synthesized and screened for their carbonic anhydrase (CA, EC 4.2.1.1) inhibitory and cytotoxic activity on human breast cancer cell line MCF-7. Human (h) CA isoforms I, II and IX were included in the study. The new sulfonamides showed excellent inhibition of all three isoforms, with KIs in the range of 0.84–702 nM against hCA I, of 0.41–288 nM against hCA II and of 5.6–29.2 against the tumor-associated hCA IX, a validated anti-tumor target, with a sulfonamide (SLC-0111) in Phase I clinical trials for the treatment of hypoxic, metastatic solid tumors overexpressing CA IX. The new compounds showed micromolar inhibition of growth efficacy against breast cancer MCF-7 cell lines. 相似文献
100.
新药原料--低毒性、抗病毒、抗肿瘤失配双链核糖核酸的研究进展聂实践胡冬琴赵红罗薇(北京市营养源研究所真菌工程实验室)前言近年来,全球性病毒性疾病在不断增加,但对抗病毒药物的研究却进展缓慢。直至今日由病毒引起的恶性疾病(如恶性肿瘤,AIDS病等)仍无法医治,这已成为当今严重的社会问题。据统计约60%的流行性传染病都是由病毒感染引起的,细菌感染仅占15%。而目前世界各国批准使用的合成抗病毒药物仅... 相似文献