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961.
Wei Tian Guangqian Han Ju Zhu Jingjing Qi Qianqian Chen Juntao Zhao Canhui Zheng Ling Zhang Youjun Zhou Jiaguo Lv 《Bioorganic & medicinal chemistry letters》2013,23(14):4177-4184
A series of novel 5-phenyl-1H-pyrazole-3-carboxylic acid amide derivatives were designed, synthesized, and their acrosin inhibitory activities in vitro were evaluated. The results of the acrosin inhibitory activity showed that all target compounds were more potent than control TLCK. Compounds AQ-A1, AQ-D3, AQ-D4, AQ-E4 and AQ-E5 exhibited stronger acrosin inhibitory activities than control ISO-1. Especially, compound AQ-E5 displayed the most potent acrosin inhibitory activity in all the compounds, with an IC50 of 0.01 μmol/mL. This study provided a new structural class for the development of novel acrosin inhibitory agents. 相似文献
962.
Guo-Liang Chen Li-Hui Wang Jian Wang Kang Chen Man Zhao Zhao-Zhu Sun Shuang Wang Hong-Li Zheng Jing-Yu Yang Chun-Fu Wu 《Bioorganic & medicinal chemistry letters》2013,23(13):3891-3895
Retinoid X receptor (RXR) and Histone deacetylase (HDAC) are considered important targets for anti-cancer therapy due to their crucial roles in genetic or epigenetic regulations of cancer development and progression. Here, we have designed and synthesized a novel compound which targets both RXR and HADC. This dual-targeting agent is derived from bexarotene and suberoylanilide hydroxamic acid (SAHA), prototypical RXR agonist and HDAC inhibitor, respectively. Molecular docking studies demonstrate that this agent has a relatively strong affinity to RXR and HADC. Importantly, it presents the potentials of activation of RXR and inhibition of HDAC in both cell-free and whole-cell assays, and displays anti-proliferative effect on representative cancer cell lines and drug-resistant cancer cell lines. 相似文献
963.
Hua Chen Shuai Li Yuchao Yao Likai Zhou Jianpeng Zhao Yunjing Gu Kerang Wang Xiaoliu Li 《Bioorganic & medicinal chemistry letters》2013,23(17):4785-4789
Novel triphenylethylene–coumarin hybrid derivatives containing different amounts of amino side chains were designed and synthesized in good yields under microwave radiation. The derivatives 5b–d which possessed two amino side chains (except morpholinyl) showed a broad-spectrum and good anti-proliferative activity against five tumor cells and low cytotoxicity in osteoblast. UV–vis, fluorescence, and circular dichroism (CD) spectroscopies and thermal denaturation exhibited that compounds 10c, 5c, and 13c bearing amino side chain (except morpholinyl) on 4-phenyl had significant interactions with Ct-DNA by the intercalative mode of binding. Structure–activity relationships (SARs) analysis suggested that the amino alkyl chain would play an important role both in the compounds against tumor cells proliferation and their interactions with DNA. 相似文献
964.
Little is known about how foreign DNA is randomly integrated into chromosomes in transgenic animals. In the current study, the insertion sites of 36 transgenic mice were mapped by thermal asymmetric interlaced PCR, and 38 junction sequences were obtained from 30 samples. Analysis of the 38 sequences revealed that 44.7 % of integration events occurred within host gene regions, including 13.2 % (5/38) in exonic regions and 31.6 % (12/38) in intronic regions. The results also revealed that all non-end side integrations of foreign DNA were mediated by short sequence homologies (microhomologies) and that the end side integrations occurred in the presence or absence of microhomologies. In addition, microhomology-mediated mechanisms were also confirmed in four transgenic Arabidopsis thaliana lines. The results indicate that foreign DNA is easily integrated into host gene regions. These results also suggest that the integration of both ends of foreign DNA follows the above-mentioned mechanism in many transgenic/transformed organisms. 相似文献
965.
966.
Xuhua Liang Yang Sun Wenyuan Zeng Lusha Liu Xuan Ma Yingyong Zhao Jun Fan 《Bioorganic & medicinal chemistry》2013,21(1):178-185
To improve the therapeutic effect of rhaponticin (RHA), a folate receptor (FR) targeted RHA conjugate was synthesized by utilizing a hydrophilic peptide spacer linked to folic acid (FA) via a releasable disulfide linker. This water-soluble conjugate was found to retain high affinity for FR-positive cells, and it produced specific, dose-responsive activity in vitro. Treatment of FRHA with a reducing agent indicated that the amino-reactive derivative of RHA would be released spontaneously following disulfide bond reduction within the endosomes. FRHA also proved to be active predominantly specific against FR-positive syngeneic and xenograft models in vivo, and possible curative activity resulted with minimal to moderate toxicity. The FRHA conjugate greatly enhanced the therapeutic effects and reduced the toxicity of RHA. In conclusion, FRHA represents a folate-targeted chemotherapeutic that can produce potent activity against established sc tumors. Hence, this report has a great significance in pharmacology and clinical medicine as well as methodology. 相似文献
967.
Chong Li Changyou Zhan Le Zhao Xishan Chen Wei-Yue Lu Wuyuan Lu 《Bioorganic & medicinal chemistry》2013,21(14):4045-4050
Peptide retro-inverso isomerization is thought to be functionally neutral and has been widely used as a tool for designing proteolytically stable d-isomers to recapitulate biological activities of their parent l-peptides. Despite success in a wide range of applications, exceptions amply exist that clearly defy this rule of thumb when parent l-peptides adopt an α-helical conformation in their bound state. The detrimental energetic effect of retro-inverso isomerization of an α-helical l-peptide on its target protein binding has been estimated to be 3.0–3.4 kcal/mol. To better understand how the retro-inverso isomer of a structured protein works at the molecular level, we chemically synthesized and functionally characterized the retro-inverso isomer of a rationally designed miniature protein termed stingin of 18 amino acid residues, which adopts an N-terminal loop and a C-terminal α-helix stabilized by two intra-molecular disulfide bridges. Stingin emulated the transactivation peptide of the p53 tumor suppressor protein and bound with high affinity and via its C-terminal α-helix to MDM2 and MDMX—the two negative regulators of p53. We also prepared the retro isomer and d-enantiomer of stingin for comparative functional studies using fluorescence polarization and surface plasmon resonance techniques. We found that retro-inverso isomerization of l-stingin weakened its MDM2 binding by 720 fold (3.9 kcal/mol); while enantiomerization of l-stingin drastically reduced its binding to MDM2 by three orders of magnitude, sequence reversal completely abolished it. Our findings demonstrate the limitation of peptide retro-inverso isomerization in molecular mimicry and reinforce the notion that the strategy works poorly with biologically active α-helical peptides due to inherent differences at the secondary and tertiary structural levels between an l-peptide and its retro-inverso isomer despite their similar side chain topologies at the primary structural level.1 相似文献
968.
Meng Zhang Liang Dong Zhubing Shi Shi Jiao Zhen Zhang Wenqing Zhang Guoguang Liu Cuicui Chen Miao Feng Qian Hao Wenjia Wang Mengxin Yin Yun Zhao Lei Zhang Zhaocai Zhou 《Structure (London, England : 1993)》2013,21(4):680-688
Highlights? Crystal structure of CCM3-MST4 heterodimeric complex ? Structural mechanism driving CCM3-GCKIII heterodimerization ? Conformational changes required for CCM3-GCKIII heterodimerization ? Synergistic effects of CCM3-MST4 complex on cell proliferation and migration 相似文献
969.
以水稻种植区的砷污染土壤为研究对象,采用高效液相色谱(HPLC)-电感耦合等离子体质谱(ICP-MS)联用分析测试系统,研究了不同培养温度(5、27和50 ℃)对灭菌和不灭菌的土壤淹水后其溶液中砷赋存形态变化的影响.结果表明: 在土壤溶液中检测到的砷形态只有无机三价砷(AsⅢ)、无机五价砷(AsV)和有机的二甲基砷(DMAV),未检测到单甲基砷(MMAV)的存在;在不同控温条件下随淹水时间的延长,AsⅢ逐渐转变为砷的主要赋存形态,平均比例约为64%;AsV次之,约占35%,DMAV的含量相对最低,约占1%;土壤灭菌与否对土壤溶液中五价砷的水平没有明显影响,但明显影响了五价砷的还原和促进了无机三价砷的甲基化,并且灭菌的促进效果随着淹水及培养时间的延长而逐渐降低;50 ℃、淹水23 d时,灭菌土壤溶液中DMAV浓度最高,为23.7 ng·mL-1,这说明灭菌土壤中残留的某些嗜热微生物成为优势菌群并促进了土壤溶液中砷的甲基化.结合水稻生长的实际环境条件对该研究结果进行分析,培养温度27 ℃淹水23 d后不灭菌的自然土壤溶液中砷浓度处于较低水平,因此在砷污染的水稻种植区建议采用短周期干湿交替的水分管理模式,在保障产量的情况下可尽量降低土壤溶液中砷的水平. 相似文献
970.
Ying Zhao Xue Li Mu-Yan Cai Ke Ma Jing Yang Jingyi Zhou Wan Fu Fu-Zheng Wei Lina Wang Dan Xie Wei-Guo Zhu 《Cell research》2013,23(4):491-507
Autophagy is activated to maintain cellular energy homeostasis in response to nutrient starvation. However, autophagy is not persistently activated, which is poorly understood at a mechanistic level. Here, we report that turnover of FoxO1 is involved in the dynamic autophagic process caused by glutamine starvation. X-box-binding protein-1u (XBP-1u) has a critical role in FoxO1 degradation by recruiting FoxO1 to the 20S proteasome. In addition, the phosphorylation of XBP-1u by extracellular regulated protein kinases1/2 (ERK1/2) on Ser61 and Ser176 was found to be critical for the increased interaction between XBP-1u and FoxO1 upon glutamine starvation. Furthermore, knockdown of XBP-1u caused the sustained level of FoxO1 and the persistent activation of autophagy, leading to a significant decrease in cell viability. Finally, the inverse correlation between XBP-1u and FoxO1 expression agrees well with the expression profiles observed in many human cancer tissues. Thus, our findings link the dynamic process of autophagy to XBP-1u-induced FoxO1 degradation. 相似文献