Chemistry, biology, and QSAR studies of substituted biaryl hydroxamates and mercaptoacetamides as HDAC inhibitors-nanomolar-potency inhibitors of pancreatic cancer cell growth

The histone deacetylases (HDACs) are able to regulate gene expression, and inhibitors of the HDACs (HDACIs) hold promise in the treatment of cancer as well as a variety of neurodegenerative diseases. To investigate the potential for isoform selectivity in the inhibition of HDACs, we prepared a small series of 2,4'-diaminobiphenyl ligands functionalized at the para-amino group with an appendage containing either a hydroxamate or a mercaptoacetamide group and coupled to an amino acid residue at the ortho-amino group. A smaller series of substituted phenylthiazoles was also explored. Some of these newly synthesized ligands show low-nanomolar potency in HDAC inhibition assays and display micromolar to low-nanomolar IC(50) values in tests against five pancreatic cancer cell lines. The isoform selectivity of these ligands for class I HDACs (HDAC1-3 and 8) and class IIb HDACs (HDAC6 and 10) together with QSAR studies of their correlation with lipophilicity are presented. Of particular interest is the selectivity of the mercaptoacetamides for HDAC6.     

Guanidinoneomycin B recognition of an HIV-1 RNA helix

Aminoglycoside antibiotics are small-molecule drugs that bind RNA. The affinity and specificity of aminoglycoside binding to RNA can be increased through chemical modification, such as guanidinylation. Here, we report the binding of guanidinoneomycin B (GNB) to an RNA helix from the HIV-1 frameshift site. The binding of GNB increases the melting temperature (T(m)) of the frameshift-site RNA by at least 10 degrees C, to a point at which a melting transition is not even observed in 2 M urea. A structure of the complex was obtained by using multidimensional heteronuclear NMR spectroscopic methods. We also used a novel paramagnetic-probe assay to identify the site of GNB binding to the surface of the RNA. GNB makes major-groove contacts to two sets of Watson-Crick bases and is in van der Waals contact with a highly structured ACAA tetraloop. Rings I and II of GNB fit into the major groove and form the binding interface with the RNA, whereas rings III and IV are exposed to the solvent and disordered. The binding of GNB causes a broadening of the major groove across the binding site.     

Ligand-directed immobilization of proteins through an esterase 2 fusion tag studied by atomic force microscopy

Atomically flat mica surfaces were chemically modified with an alkyl trifluoromethyl ketone, a covalent inhibitor of esterase 2 from Alicyclobacillus acidocaldarius, which served as a tag for ligand-directed immobilization of esterase-linked proteins. Purified NADH oxidase from Thermus thermophilus and human exportin-t from cell lysates were anchored on the modified surfaces. The immobilization effectiveness of the proteins was studied by atomic force microscopy (AFM). It was shown that ligand-esterase interaction allowed specific attachment of exportin-t and resulted in high-resolution images and coverage patterns that were comparable with immobilized purified protein. Moreover, the biological functionality of immobilized human exportin-t in forming a quaternary complex with tRNA and the GTPase Ran-GTP, and the dimension changes before and after complex formation were also determined by AFM.     

新型700 MPa级高强锚杆钢的微观组织及强化机制

自主设计了700 MPa级高强锚杆钢,采用光学显微镜、扫描电镜和透射电镜等对其微观组织与性能进行了系统测试与表征,并进一步讨论了其强化机制。结果表明,该锚杆用钢的显微组织为珠光体和铁素体复相组织,铁素体呈细小的等轴状,珠光体呈长条形片层状分布,组织中珠光体体积分数约为43%;铁素体基体上析出了大量小于20 nm的纳米级V(C, N)粒子;试验钢屈服强度约为734 MPa,抗拉强度约为936 MPa,断后伸长率约为15.1%,屈强比约为0.78,具有良好的综合性能;该锚杆钢的强化机制为细晶强化、固溶强化、位错强化及析出强化的耦合强化,其中,细晶强化及固溶强化引起的强度贡献约占总强度值的73%。     

铸铝自冲铆接接头裂纹扩展行为研究及仿真预测北大核心CSCD

为了研究铸铝在自冲铆接工艺中的裂纹扩展行为,以5754铝板和Aural2铸铝为搭接组合的自冲铆接接头为研究对象,通过中断试验近似还原了接头剖面裂纹产生的位置和裂纹形貌,讨论了自冲铆接过程中接头内部铸铝材料的裂纹扩展机制,并进行了仿真分析,开展了几何形貌和裂纹预测。结果表明,铸铝自冲铆接接头裂纹产生的位置主要有两处:一处位于自冲铆接接头底面与模具接触一侧,裂纹在铆钉刚接触下板时产生,随着铆钉压入而增多;另一处位于铆钉钉腿与上下板形成互锁处的下板铸铝材料上,裂纹在形成互锁过程中产生,随着铆钉下压不断增长。建立的基于GISSMO损伤失效的铆接仿真模型,仿真结果的形貌轮廓与试验剖面的几何形貌一致,单元损伤与接头裂纹一致,可以对接头剖面几何形貌和裂纹位置进行准确预测。     

采用BNi-5钎料钎焊K417G高温合金的界面组织和力学性能

K417G镍基高温合金具有优异的高温力学性能,可应用于航空发动机热端部件的制造中。采用BNi-5镍基钎料开展了K417G合金钎焊接头的研究,分析了不同保温时间对钎焊接头微观组织演变和接头高温力学性能的影响。在1 160℃保温15 min条件下,K417G合金接头界面处物相主要由γ+γ’相、富Ti碳化物相和(Ni,Cr)3Si相等物相组成。随着保温时间的进一步延长,界面反应和元素扩散更为充分;同时接头中的硅化物相分布呈分散趋势,物相尺寸得到细化。1 160℃×30 min条件下获得的接头950℃平均抗拉强度为412 MPa。     

用原位有机改性法制备的溴化丁基橡胶／蒙脱土复合材料的性能

采用原位有机改性法制备了溴化丁基橡胶(BIIR)/蒙脱土(MMT)复合材料,并对其硫化特性和力学性能进行了研究,用X射线衍射仪时复合材料中MMT的层间距进行了表征,并与钠基蒙脱土(Na-MMT)、有机蒙脱土(OMMT)和BIIR形成的复合材料进行了对比.结果表明,用原位有机改性法制备的BIIR/MMT复合材料的硫化特性和力学性能优于BIIR/Na/MMT复合材料,甚至优于BIIR/OMMT复合材料;采用原位有机改性法,可使BIIR/MMT体系中MMT的插层效果明显改善.     

原位生成丙烯酸锂改性丁腈橡胶抗静电性能的研究

用丁腈橡胶(NBR)作基体,分别研究了在NBR中原位生成丙烯酸锂(LiAA)及在NBR/LiAA中添加氯化镧(LaCl3)后,硫化胶体系电学性能的变化.结果表明,在NBR中原位生成LiAA,可降低NBR的体积电阻率,使其由绝缘材料转变为抗静电材料;进一步在NBR/LiAA中添加LaCl3,体系体积电阻率继续降低,在LaCl3用量为20份左右时,体系体积电阻率有一最低值并趋于稳定.     

乙基硅橡胶低温性能的研究

研究了乙基硅橡胶的低温性能.试验表明,乙基硅橡胶在-100 ℃下的压缩耐寒系数为0.49,经1 h压缩冷冻后为0.45;而苯基硅橡胶在-100 ℃下的压缩耐寒系数为0.04,经1 h压缩冷冻后为0.DMTA分析结果表明,乙基硅橡胶的玻璃化转变温度为-147 ℃,比苯基硅橡胶的玻璃化转变温度(-123 ℃)低24 ℃,显示了优异的耐超低温性能.     

聚合物水下切粒模板温度场的数值模拟研究

建立了7种不同模孔和3种不同加热油流道水下切粒模板的三维传热模型,并对各个模型进行了数值求解,获得了各个模板模型内部的温度场;并且计算了在不同温度的冷却水、不同的加热油的对流换热系数、不同模板材料下的模板的温度场。计算结果表明,由于受到冷却水的冷却作用,各模板切粒带表层处温度比较低;沿着厚度方向,由于受到加热油和聚合物的加热作用,切粒带深层的温度逐渐升高;在加热油加热和冷却水冷却共同作用下,在0≤z≤10mm处,切粒面浅层的温度梯度较大。通过分析,模孔尺寸对模板的温度场基本没有影响;加热油流道形式、冷却水的温度、加热油的对流换热系数和模板的材料对模板的温度场有一定的影响,这为模板的结构设计、边界条件的确定和模板材料的选择提供了可靠的理论依据。