DNA-Directed alkylating agents. 7. Synthesis, DNA interaction, and antitumor activity of bis(hydroxymethyl)- and bis(carbamate)-substituted pyrrolizines and imidazoles

A series of bis(hydroxymethyl)-substituted imidazoles, thioimidazoles, and pyrrolizines and related bis(carbamates), linked to either 9-anilinoacridine (intercalating) or 4-(4-quinolinylamino)benzamide (minor groove binding) carriers, were synthesized and evaluated for sequence-specific DNA alkylation and cytotoxicity. The imidazole and thioimidazole analogues were prepared by initial synthesis of [(4-aminophenyl)alkyl]imidazole-, thioimidazole-, or pyrrolizine dicarboxylates, coupling of these with the desired carrier, and reduction to give the required bis(hydroxymethyl) alkylating moiety. The pyrrolizines were the most reactive alkylators, followed by the thioimidazoles, while the imidazoles were unreactive. The pyrrolizines and some of the thioimidazoles cross-linked DNA, as measured by agarose gel electrophoresis. Strand cleavage assays showed that none of the compounds reacted at purine N7 or N3 sites in the gpt region of the plasmid gpt2Eco, but the polymerase stop assay showed patterns of G-alkylation in C-rich regions. The corresponding thioimidazole bis(carbamates) were more selective than the bis(hydroxymethyl) pyrrolizines, with high-intensity bands at 5'-NCCN, 5'-NGCN and 5'-NCGN sequences in the PCR stopping assay ( indicates block sites). The data suggest that these targeted compounds, like the known thioimidazole bis(carbamate) carmethizole, alkylate exclusively at guanine residues via the 2-amino group, with little or no alkylation at N3 and N7 guanine or adenine sites. The cytotoxicities of the compounds correlated broadly with their reactivities, with the bis(hydroxymethyl)imidazoles being the least cytotoxic (IC50s >1 microM; P388 leukemia) and with the intercalator-linked analogues being more cytotoxic than the corresponding minor-groove-targeted ones. This was true also for the more reactive thioimidazole bis(carbamates) (IC50s 0.8 and 11 microM, respectively), but both were more active than the analogous "untargeted" carmethizole (IC50 20 microM). The bis(hydroxymethyl)pyrrolizine analogues were the most cytotoxic, with IC50s as low as 0.03 microM.     

冲击式机组动能参数在线监测

鉴于冲击式水轮机结构上的特殊性,其流量效率等动能参数在线监测目前在国内还是项空白,针对冲击式机组的具体情况,探讨了基于压差理论的监测途径,在此基础上结合一个冲击式电站的实例,设计出了利用单片机来实现的方案．     

图的正交(g,f)-因子分解

设ｇ和ｆ分别是定义在图Ｇ的顶点集合Ｖ（Ｇ）上的整数值函数且对每一个ｘ∈Ｖ（Ｇ）有２≤ｇ（ｘ）≤ｆ（ｘ）．证明了若Ｇ是（ｍｇ＋ｍ－１,ｍｆ－ｍ＋１）—图,则对Ｇ中任意一个给定的有ｍ条边的子图Ｈ,Ｇ有一个（ｇ,ｆ）—因子分解与Ｈ正交．     

“迭代-降维-梯度搜索法”求解Dobbins模型参数研究

文章介绍了用“迭代－降维－梯度搜索法”求解Dobbins模型参数的研究成果。该法能解决目前存在的用梯度法搜索参数时误差较大及用“计算机扫描计算－图解－梯度搜索法”寻求参数时计算量较大的问题。     

建筑施工与管理专业教学计划整体构想

借鉴CBE/DACUM教育模式,提出了我国高等工程专科学校教育目标确定的方法,并就建筑施工与管理专业理论教育内容、职业能力的培养、学校与企业合作培养人才机制进行了研究,确定了专业人才培养目标模式和课程体系。     

正确把握“三个环节” 做好经常性思想工作

“及时发现,确实弄清,正确解决”是做好经常性思想工作的３个基本环 节。“及时发现”是做好经常性思想工作的前提,要做到及时发现,一要把握规律,搞好 预测;二要留心观察,掌握细微;三是个别交谈,讲究艺术;四要摸底测试,搞好普查; 五是会议收集,全面分析。“确实弄清”是做好经常性思想工作的关键,一要搞好调查 研究,弄清思想问题的真正原因;二要进行科学分析,弄清思想问题的本质。“正确解 决”是做好经常性思想工作的目的,一要动之以情;二要晓之以理;三要喻之以义;四 要导之以行。     

板坯连铸辊失效原因及其修复技术

首先介绍连铸辊失效的基本形式,提出了极限寿命的概念及开展修复的意义．然后从不同角度分析了辊子裂纹产生的影响因素,并给出实际断口的典型形貌．最后就目前常用的修复方法进行了比较,提出修复新方法设想．     

两类古典概率的阶乘近似计算

改进了一个阶乘的不等式,并在此基础上,对有关含有阶乘的两类古典概率二项分布和超几何分布的近似计算问题进行了讨论．     

强化财务成本控制 促进经济效益提高

在海南气体处理厂工程项目中,中海石油平台制造公司在总结以往单项工程财务管理经验的基础上,认真分析了该项目的特点,在财务管理上进行了大胆的探索与改革,即对整个工程实行了“施工全过程的成本控制管理”,采取了按部门控制费用的措施;充分发挥了计算机在财务管理上的作用;财务人员深入各部门和施工现场,掌握工程施工情况,更好地控制成本,跟踪并及时反馈核算情况;准确掌握税收政策,避免重复纳税,使承包工程取得很好的经济效益。     

ZrO2在β"─Al2O3复合陶瓷中的作用

本文研究了四方和立方ZrO₂在与Na-β"-Al₂O₃的复合陶瓷中作为第二相所起的各种作用。结果说明ZrO₂对复合陶瓷具有细化晶粒、改善显微结构、提高强度和断裂韧性的作用,与此同时也在一定程度上降低离子电导率。在提高力学性能方面,四方ZrO₂除了具有与立方ZrO₂相同的弥散颗粒的作用外,相变所起的作用也是很显着的。ZrO₂-Na-β"-Al₂O₃复合陶瓷是一种有应用价值的固体电解质材料。