Design,Synthesis, and Biological Evaluation of Orally Bioavailable CHK1 Inhibitors Active against Acute Myeloid Leukemia

Checkpoint kinase 1 (CHK1) is a central component in DNA damage response and has emerged as a target for antitumor therapeutics. Herein, we describe the design, synthesis, and biological evaluation of a novel series of potent diaminopyrimidine CHK1 inhibitors. The compounds exhibited moderate to potent CHK1 inhibition and could suppress the proliferation of malignant hematological cell lines. The optimized compound 13 had a CHK1 IC₅₀ value of 7.73±0.74 nM, and MV-4-11 cells were sensitive to it (IC₅₀=0.035±0.007 μM). Furthermore, compound 13 was metabolically stable in mouse liver microsomes in vitro and displayed moderate oral bioavailability in vivo. Moreover, treatment of MV-4-11 cells with compound 13 for 2 h led to robust inhibition of CHK1 autophosphorylation on serine 296. Based on these biochemical results, we consider compound 13 to be a promising CHK1 inhibitor and potential anticancer therapeutic agent.     

Design,Synthesis, and Biological Evaluation of 2-Aminothiazole Derivatives as Novel Checkpoint Kinase 1 (CHK1) Inhibitors

A series of 2-aminothiazole derivatives were designed, synthesized on the basis of bioisosterism strategy and evaluated for their CHK1 inhibitory activity. Most of them exhibited potent CHK1 inhibition, and excellent antiproliferative activity against MV-4-11 and Z-138 cell lines. Systematic structure-activity relationship (SAR) efforts led to the discovery of a promising compound 8 n , which showed potent CHK1 inhibitory activity with IC₅₀ value of 4.25±0.10 nM, excellent antiproliferative activity against MV-4-11 and Z-138 cells with IC₅₀ value of 42.10±5.77 nM and 24.16±6.67 nM, respectively, as well as moderate oral exposure (AUC_(0−t)=1076.25 h ⋅ ng/mL) in mice. Additionally, treatment of MV-4-11 cells with compound 8 n for 2 h led to robust inhibition of CHK1 autophosphorylation on serine 296. Furthermore, kinase selectivity assay revealed that 8 n displayed acceptable selectivity toward 15 kinases. These results demonstrated that compound 8 n may be a promising potential anticancer agent for further development.     

聚氯乙烯/蒙脱土纳米复合材料性能的研究

利用低聚有机蒙脱土(OMMT)与聚氯乙烯(PVC)基质通过熔融共混法制备(PVC/OMMT)纳米复合材料。通过X射线衍射(XRD)、透射电子显微镜(TEM)表征了两种复合材料的微观结构和形貌,通过热重分析测试和热变形温度测试探讨了材料的热性能,并对材料的力学性能进行了测试和讨论。结果表明:PVC分子链段插入了OMMT层间;在OMMT质量分数为0.5%时,耐热性提高了7℃;热变形温度提高了约3℃;拉伸强度增加了9.9%;断裂伸长率提高了17.0%。     

釉料组成对骨质瓷热稳定性及抗折强度的影响

骨质瓷作为高级日用细瓷之一,以其高白度、高透光度和高强度等优良性能在国内外市场深受青睐。但骨质瓷的热稳定性远不如传统的K2O-Al2O3-SiO2系统瓷及滑石质日用细瓷。通常日用细瓷对热稳定性要求是制品水中交换温差达到200℃以上;而目前我国实际生产的骨质瓷制品水中交换温差多在140℃以下,即便是优质的骨质瓷水中交换的温差也只是达到160℃。国内外对提高骨质瓷热稳定性进行了大量的研究,笔者在此基础上探讨釉料组成对骨质瓷热稳定性的影响。笔者就釉料的作用与特点进行了简单介绍,阐述了釉料配置应遵循的原则以及各氧化物在釉料中的作用。其着重计算了基础釉料配方以及调整组成后的各组配方的膨胀系数,及其与坯体膨胀系数的差值,介绍了釉浆制备及施釉工艺;着重叙述了各组配方烧成曲线及温度的确定,以及测定各组烧成试样的热稳定性、白度、抗折强度及坯釉适应性等性能的实验过程和实验结果,并进行简要的分析。最后,通过总实验结果的分析与讨论,得出结论,即通过改变釉料组成提高热稳定性是可行的。